Fimmu 13 961805

TYPE Review
PUBLISHED 11 October 2022

DOI 10.3389/fimmu.2022.961805
Clinical cancer immunotherapy:

OPEN ACCESS Current progress and prospects
EDITED BY
Catherine Sautes-Fridman,
INSERM U1138 Centre de Recherche Chenglong Liu 1, Mengxuan Yang 1, Daizhou Zhang 2,
des Cordeliers (CRC), France
Ming Chen 3,4 and Di Zhu 1,2,5*
REVIEWED BY
Hongji Zhang, 1
Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University,
University of Virginia, United States Shanghai, China, 2 New Drug Evaluation Center, Shandong Academy of Pharmaceutical Science,
Firas Hamdan, Jinan, China, 3 Department of Laboratory Medicine, Sixth Affiliated Hospital of Yangzhou University,
University of Maryland, Baltimore, Yangzhou, China, 4 Department of Laboratory Medicine, Affiliated Taixing Hospital of Bengbu
United States Medical College, Taizhou, China, 5 Shanghai Engineering Research Center of ImmunoTherapeutics,
Kohichi Takada, Fudan University, Shanghai, China
Sapporo Medical University, Japan
*CORRESPONDENCE
Di Zhu
[email protected] Immune checkpoint therapy via PD-1 antibodies has shown exciting clinical
SPECIALTY SECTION value and robust therapeutic potential in clinical practice. It can significantly
This article was submitted to improve progression-free survival and overall survival. Following surgery,
Cancer Immunity
and Immunotherapy, radiotherapy, chemotherapy, and targeted therapy, cancer treatment has
a section of the journal now entered the age of immunotherapy. Although cancer immunotherapy
Frontiers in Immunology
has shown remarkable efficacy, it also suffers from limitations such as irAEs,
RECEIVED 05 June 2022 cytokine storm, low response rate, etc. In this review, we discuss the basic
ACCEPTED 26 September 2022
PUBLISHED 11 October 2022
classification, research progress, and limitations of cancer immunotherapy.
Besides, by combining cancer immunotherapy resistance mechanism with
CITATION
Liu C, Yang M, Zhang D, Chen M analysis of combination therapy, we give our insights into the development
and Zhu D (2022) Clinical cancer of new anticancer immunotherapy strategies.
immunotherapy: Current
progress and prospects.
Front. Immunol. 13:961805. KEYWORDS
doi: 10.3389/fimmu.2022.961805 immunotherapy, tumor microenvironment, immune checkpoint inhibitors, CAR-T,
COPYRIGHT cancer vaccines
© 2022 Liu, Yang, Zhang, Chen and
Zhu. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original author
(s) and the copyright owner(s) are
credited and that the original Introduction
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
Cancer immune surveillance is an important process by which the immune system
reproduction is permitted which does can identify and eliminate nascent tumor cells (1). Normally, when tumor cells invade
not comply with these terms. healthy tissue, the immune system can recognize and eliminate them based on tumor-
associated antigens (TAAs). However, tumor cells can evade the immune system through
a variety of mechanisms called immune escape (2). There are four main mechanisms: 1)
decreasing immunogenicity by down-regulating surface antigen expression; 2) up-
regulating immune checkpoints on the surface for suppressing T-cell activity; 3)
recruiting suppressor immune cells such as myeloid-derived suppressor cells (MDSCs)
and regulatory T cells (Treg) as well as cytokines to form a suppressive immune
microenvironment; 4) releasing acidic and toxic metabolites that inhibit the activity of
immune cells in the tumor microenvironment (3).
Frontiers in Immunology 01 frontiersin.org

Liu et al. 10.3389/fimmu.2022.961805
Cancer is the second-leading cause of human death after receptors on the surface of immune cells. All mAbs exert their
cardiovascular and cerebrovascular diseases, and the number of function by direct targeting via Fab terminals. Additionally, Fc-Fc
patients continues to increase. Cancer treatment has progressed receptor (FcR) interaction can modulate their modes of action
from surgical resection, radiation therapy, chemotherapy, and (MOA) (6, 7). The main Fc-mediated effector functions are
targeted drug therapy to immunotherapy. Cancer immunotherapy classified into complement-dependent cytotoxicity (CDC),
reactivates the body’s immune system to produce anticancer effects antibody-dependent cell-mediated cytotoxicity (ADCC), and
and thus kills and eliminates tumor cells. Immunotherapy is a antibody-dependent cellular phagocytosis (ADCP). CDC is
promising treatment. Different from traditional therapy, attributed to the Fc interaction with complement component C1q,
immunotherapy uses some cytokines, chemokines, and immune followed by the activation of the complement system leading to the
cells to reshape the tumor microenvironment, which can lead to downstream immune responses on different immune cells (8, 9).
robust effects and prevent recurrence (4, 5). The emergence of ADCC and ADCP are two mechanisms mediated by the direct
immunotherapy has changed the standard and concept of tumor interaction of Fc and FcgR. ADCC is mainly attributed to NK cells
treatment. This article focuses on the latest clinical progress in cancer activated by the interaction of FcgRIIIa with the mAb’s Fc part.
immunotherapy, including monoclonal antibodies (mAbs), small ADCP is mediated by FcgIIa-activated macrophages, which can
molecule drugs, adoptive cell therapy, oncolytic viruses, and cancer phagocytose antibody-bounded tumor cells, leading to the
vaccines (Figure 1). We discuss limitations, immune resistance, and elimination of tumor cells (8, 9). In other MOAs, mAbs are used
combination strategies in this review and hope to give a promising to bind and block, such as soluble antigens (e.g., a- tumor necrosis
outlook for the future development of cancer immunotherapy. factor (TNF-a)) and disease-dependent pathological mediators (e.g.,
vascular endothelial growth factor (VEGF)). Since rituximab targeting
Monoclonal antibody therapy CD20 was first approved for Non-Hodgkin’s lymphoma (NHL) in
1997, the US Food and Drug Administration (FDA) has approved a
Therapeutic mAbs variety of therapeutic monoclonal antibodies, which can target CD19,
HER-2, VEGFA, EGFR, and CD52, etc. (Table 1).
mAbs are immunoglobulins (Ig) which commonly include two Besides non-conjugated mAbs targeting ‘naked’ antigens,
Fab terminals binding to targets and an Fc terminal binding to antibody-drug conjugates (ADCs) have shown promising
FIGURE 1
Cancer immunotherapy methods, including monoclonal antibodies (mAbs), small molecule drugs, adoptive cell therapy, oncolytic virus, and
cancer vaccines. CAR, chimeric antigen receptor. CXCR, C-X-C motif chemokine receptor. TAAs, tumor-associated antigens. ADCC, antibody-
dependent cell-mediated cytotoxicity. PD-1, programmed death-1. PD-L1, programmed death-ligand 1. CTLA-4, cytotoxic T-lymphocyte-
associated protein 4.

Liu et al. 10.3389/fimmu.2022.961805
therapeutic effects. ADCs show direct cytotoxicity based on their hematological tumors. The microenvironment of solid tumors
payloads, which can be ingested through the endocytosis of and other factors make it difficult for mAbs to penetrate. In this
receptor-bound ADCs. Among the ADCs approved by the FDA, regard, the accessibility of hematological tumors is better, which
the indications of targets including CD22, CD30, CD33, CD79b, is the key factor why therapeutic mAbs will make breakthroughs
and BCMA are hematological tumors. Besides, HER2, Nectin-4, in the field of hematological tumors first. But now, ADCs also
and Trop-2 are indicated for solid tumors. In terms of target show promising results for the treatment of solid tumors after
accessibility, solid tumors are more obstructive than the optimization of antibodies, linkers, and payloads. In a phase
TABLE 1 FDA-approved mAbs (Up to March 2022).
Therapeutic mAb
Target Name Company Year of launched Mechanism of Action
CD20 Rituximab Roche 1997 CDC, ADCC, ADCP

CD20 Ofatumumab Novartis 2009 CDC, ADCC, ADCP
CD20 Obinutuzumab Roche 2013 ADCC, ADCP
CD19 Tafasitamab MorphoSys & Incyte 2020 CDC, ADCC, ADCP
CD19 Loncastuximab tesirine ADC Therapeutics 2021 Cytotoxic drug delivery
CD52 Alemtuzumab Genzyme 2007 CDC, ADCC, ADCP
CD79b Polatuzumab vedotin Roche 2019 Cytotoxic drug delivery
CD33 Gemtuzumab ozogamicin Pfizer 2017 Cytotoxic drug delivery
CD38 Isatuximab Sanofi 2020 CDC, ADCC, ADCP
CD22 Moxetumomab pasudotox AstraZeneca 2018 Cytotoxic drug delivery
CD30 Brentuximab vedotin Seagen 2011 Cytotoxic drug delivery
CCR4 Mogamuizumab Kyowa Kirin 2018 CDC, ADCC, ADCP
BCMA Belantamab mafodotin GSK 2020 Cytotoxic drug delivery
HER-2 Trastuzumab Roche 1998 CDC, ADCP
HER-2 Ado-Trastuzumab emtansine Roche 2013 Cytotoxic drug delivery
HER-2 [fam]-trastuzumab deruxtecan Daiichi-Sankyo 2019 Cytotoxic drug delivery
&AstraZeneca
HER-2 Margetuximab MacroGenics 2020 ADCC, ADCP
EGFR Cetuximab Merck 2004 Signal blockade, CDC, ADCC
EGFR Panitumumab AMGEN 2006 Signal blockade
EGFR Necitumumab Lilly 2015 Signal blockade, ADCC
VEGFA Bevacizumab Roche 2004 Signal blockade
VEGFR Ramucirumab Lilly 2014 Signal blockade
Nectin-4 Enfortumab vedotin Astellas 2019 Cytotoxic drug delivery
TROP-2 Sacituzumab govitecan Gliead 2020 Cytotoxic drug delivery
Bispecific mAb
Target Name Company Year of launched
CD19/CD3 blinatumomab AMGEN 2014
FIX/FX emicizumab Roche 2017
EGFR/METR amivantamab J&J 2021
Immune checkpoint mAb
Target Name Company Year of launched
CTLA-4 Ipilimumab Bristol-Myers Squibb 2011
PD-1 Pembrolizumab Merck 2014
PD-1 Nivolumab Bristol-Myers Squibb 2014
PD-1 Cemiplimab Sanofi/Regeneron 2018
PD-L1 Atezolizumab Roche 2016
PD-L1 Avelumab Merck/Pfizer 2017
PD-L1 Durvalumab AstraZeneca 2017
LAG-3 Relatlimab Bristol-Myers Squibb 2022 (Orphan Drug)

Liu et al. 10.3389/fimmu.2022.961805
II clinical trial for HER-2-overexpressing or HER-2-mutated cells. Blinatumomab produced by AMGEN is the first FDA-approved
NSCLC (NCT03505710), the results showed that the ORR of bsAb that can specifically target the CD19 of tumor cells and the CD3
Enhertu ([fam]-trastuzumab deruxtecan, an HER-2 ADC) was of T cells (Table 1). The clinical results of blinatumomab show that
61.9% and the median PFS was 14 months. In a phase I clinical the response rate of patients after treatment reaches 72%, and the
trial of triple-negative breast cancer (TNBC), the initial objective average life expectancy is more than nine months. Currently,
response rate (ORR) was 43%, the complete or partial response amivantamab (targeting EGFR/METR) has also been approved for
(CR/PR) was confirmed in 5 patients, and the disease control the treatment of non-small cell lung cancer (NSCLC) with EGFR
rate (DCR) was 95% among 21 evaluable patients treated with exon 20 insertion mutations. Another approved bsAb, emicizumab, is
datopotamab deruxtecan (a Trop-2 ADC). being used to treat hemophilia. In addition to the three bsAbs already
The structure of mAb determines its MOA. Fc-engineering on the market, clinical studies of nearly 100 bsAbs are ongoing, which
methods are used to endow therapeutic mAbs with stronger are mainly in the field of tumor therapy (12, 13). Among the bsAbs
antitumor and immune activation abilities, which are achieved under clinical research, MEDI5752 developed by AstraZeneca is a
through amino acid mutation and glycosylation modification. monovalent bsAb that can target both PD-1 and CTLA-4. The results
Tafasitamab is a therapeutic mAb targeting CD-19 with of the clinical trial (NCT03530397) have shown that MEDI5752
upregulated MOA activity through Fc-related modifications. exhibits promising antitumor activity and durable clinical benefit in
S239D and I332E mutations were performed in tafasitamab to the treatment of patients with advanced solid tumors who are not
enhance ADCC and ADCP. In the RE-MIND study, the ORR of eligible for standard therapy, with an objective response rate (ORR) of
tafasitamb combined with lenalidomide was 67.1%, and the CR 19.8% and a median duration of response (DOR) of 17.5 months
was 39.5%, which was much higher than that of the control (AACR 2022, Abstract#CT016). AFM13 developed by Affirmed can
group treated with lenalidomide singly. simultaneously bind to CD30 of lymphoma cells and CD16A of
In several patients, the mAb-induced severe or partially life- natural killer (NK) cells to kill lymphoma cells without costimulatory
threatening side effects were caused by a cytokine storm. In some signals. The results of the clinical trial (NCT03192202) of AFM13
cases caused by anti-CD20 mAb rituximab, it is assumed that the have shown that 53% of patients had a complete response (CR), 37%
excessive activation of the complement system and the had a partial response (PR), and progression-free survival (PFS) and
subsequent lysis of the targeted CD20+ cells, as well as the Fc- overall survival (OS) were 58% and 79%, respectively (AACR
FcgR interactions with recruited macrophages, lead to a strong 2022, Abstract#CT003).
cytokine secretion (10, 11). While the side effects of mAbs Although bsAb is a very promising immunotherapy
therapy can be significantly less toxic than that of traditional treatment, there are still problems. The manufacturing of
chemotherapy, mAbs can still pose a significant risk to patients. bsAbs is time-consuming and costly. There are bsAb-specific
Using the Fc-engineering strategy to reduce the immunogenicity byproducts, such as mispaired products, undesired fragments,
of mAbs will provide new ideas for future development. Due to and higher levels of aggregates. Additional purification strategies
the large molecular weight, mAbs can only be administered by are needed to be designed to obtain products of high purity. At
injection, which will lead to poor compliance for patients who the same time, more clinical trials are needed to explore the
require long-term treatment. Compared to mAbs, nanobody optimal route of administration and optimal dose to increase the
without Fc terminal has higher tissue permeability and lower concentration in target tissues and reduce systemic side effects
production cost, which makes it become the key to succeed in (14). In addition, bsAbs targeting solid tumors are very
mAbs development. In addition to being used singly, therapeutic challenging because of the adverse effects on normal tissues or
antibodies are often combined with chemotherapy drugs and other complicated factors such as inadequate penetration (12).
targeted therapy drugs. MAbs therapy will always be an
important concept for tumor treatment. Further analyses will
contribute to the design of safer therapeutic mAbs with fewer Immune Checkpoint mAbs
side effects and higher efficacy profiles in the future.
There are immune checkpoints on the surface of T cells that can
regulate the immune system. They play a negative regulatory role to
Bispecific mAbs prevent excessive activation of T cells to avoid autoimmune damage.
However, tumor cells can use these immune checkpoints to suppress
Bispecific mAbs (bsAbs) can bind multiple targets at the same the immune response, thus performing immune escape and allowing
time and have a better antitumor effect. Compared with ordinary tumor cells to escape the clearance of the immune system (15).
mAbs, bsAbs offer better stability, higher specificity, and fewer side Immune checkpoint mAbs can restore the relevant functions of T
effects. They offer significant effects in clinical treatment. BsAbs are cells by blocking immune checkpoints and releasing the “brake” of
divided into two types: those that target multiple TAAs and those that the immune system (16). More than ten immune checkpoints have
engage T cells. They can produce multiple stimulations or inhibition been discovered, and CTLA-4 and PD-1 are the most widely
effects, or recruit and activate more immune cells to eliminate tumor studied (Table 1).

Liu et al. 10.3389/fimmu.2022.961805
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a CTLA4 and PD-1 antibodies (23).. In some preclinical studies,
member of the CD28-B7 Ig superfamily. It is expressed on the anti-TIM-3 therapy can improve anti-tumor efficacy, and
surface of activated T cells and can act as an immune checkpoint to combination therapy with anti-PD-1 or anti-PD-L1 can
downregulate immune responses, thereby inhibiting the significantly reduce tumor burden and improve anti-tumor
proliferation and activation of T cells (17, 18). In 2014, the FDA immune responses (24). Several antibodies targeting TIM-3
approved ipilimumab, a mAb targeting CTLA-4, for the treatment are currently being tested in clinical trials singly or in
of melanoma; it significantly improved patient survival (19). Lynch combination to treat acute myeloid leukemia or solid tumors
and colleagues improved PFS in patients with NSCLC using (NCT04150029, NCT03680508, and NCT03099109). BsAbs
ipilimumab in combination with paclitaxel and carboplatin (20). targeting two immune checkpoints (PD-1&CTLA-4, PD-
In addition to CTLA-4, programmed death-1 (PD-1) is another 1&LAG-3, and PD-1&TIM-3) simultaneously have also been
immune checkpoint molecule expressed on the surface of T cells. Its developed. In light of the positive clinical efficacy already noted
ligand (programmed cell death ligand 1 (PD-L1)) is expressed on in combination therapy targeting immune checkpoints, the
the surface of various tumor cells (15, 21). mAb targeting the PD-1/ outcomes of clinical trials with bsABs are promising.
PD-L1 pathway can relieve immunosuppression to enhance T cell In terms of adverse reactions, immune checkpoint therapy
activity and kill tumor cells. In 2014, the FDA approved does not cause cytotoxic reactions such as myelosuppression,
pembrolizumab for the treatment of multiple cancers, including vomiting, and alopecia, but it can cause immune-related adverse
NSCLC, melanoma, and bladder cancer (16, 22). In current clinical events (irAEs) due to the activation of T cells, which can be
use, PD-1/PD-L1 mAbs combined with chemotherapy or targeted reduced by glucocorticoids and disappear after drug
therapy have achieved remarkable results. A phase III clinical trial of discontinuation. Most irAEs are always reversible (25, 26). The
NSCLC (NCT02998528) with nivolumab combined with overall incidence of irAEs was lower than that of chemotherapy-
chemotherapy was promising, and there were event-free survival induced adverse events (27). Most irAEs are grades 1/2, while
(EFS) and pathological complete response (pCR) dual-positive grades 3/4 irAEs are less frequent (28, 29). Common irAEs
outcomes (AACR 2022, Abstract#CT012). AstraZeneca include cutaneous toxicity and endocrinological disturbance,
announced the results of a clinical trial (NCT03899610) while less common but serious irAEs include pulmonary
combining durvalumab and tremelimumab in advanced epithelial toxicity, renal toxicity, hepatitis, and gastrointestinal
ovarian cancer (targets PD-L1 and CTLA-4, respectively): the ORR disturbance. Rare irAEs include type 1 diabetes, cardiac,
was 86.7%, and the ratio of TIL, CD8, and CD8/Foxp3 in TME was neurological, and hematologic-related toxicity (30, 31).
significantly increased (AACR 2022, Abstract#CT010). Fc- Besides, immune checkpoint therapy only has significant
engineering strategies are also performed in immune checkpoint effects in some patients. The premise of its effect is that the
mAbs. Theoretically, since PD-L1 is expressed on tumor cells, expression level of immune checkpoints is relatively high in
retaining ADCC activity of mAbs can simultaneously utilize the patients. Therefore, it is necessary to carry out genetic screening
killing effect of NK cells to enhance the anti-tumor effect. This of patients and apply immune checkpoint therapy to
provides a new idea for us to use immune checkpoint mAbs to exert eligible patients.
new MOAs. Only avelumab, a PD-L1 mAb, is designed with strong
ADCC activity currently. Other immune checkpoints expressed on
tumor cells can also learn from the design strategy of avelumab,
which may greatly improve antitumor activity. For PD-1 mAbs Small molecule drug
(e.g., Durvalumab), removing FcgR affinity is beneficial to attenuate immunotherapy
the ADCC effect, which is beneficial to preclude FcgR1 mediated
binding to macrophages/myeloid-derived suppressor cells Small molecule targeting PD-1/PD-L1
(MDSCs)-a potential mechanism by which PD-1-bound T cells
may be cleared. Immune escape is an important means for tumor cells to escape
More immune checkpoints continue to be discovered, such from being eliminated. Due to the abnormal immune surveillance
as TIM-3, LAG-3, and TIGIT. LAG-3 can bind its canonical mediated by immune checkpoints, tumor cells form immune escape
ligand (MHC-II) to downregulate T cell activity. A phase II/III and then obtain unlimited proliferation ability, thus leading to
clinical trial (NCT03470922) demonstrated that the median PFS tumorigenesis. MAbs therapy suffers from poor tissue penetration,
of the relatlimab plus nivolumab group was 10.12 (6.37 to 15.74), a long half-life, and high production costs. Thus, researchers are
which was over 2-fold compared to the nivolumab group (4.63 trying to develop small molecule inhibitors targeting immune
(3.38-5.62)). Currently, Opdualag (nivolumab+relatlimab) is the checkpoints. Most inhibitors are currently in the early development
first LAG-3 antibody therapy approved by the FDA and the first stage (Table 2). CA-170 developed by Aurigene and Curis has made
innovative cancer immunotherapy approved for a new immune the fastest progress and entered phase II clinical trial (CTRI/2017/12/
checkpoint in nearly 10 years. LAG-3 antibody is the third 011026) (32). CA-170 targets PD-1/PD-L1 and VISTA pathways,
immune checkpoint inhibitor approved for marketing after thus leading to the proliferation and activation of T cells to produce

Liu et al. 10.3389/fimmu.2022.961805
cytokines such as IFN-g to kill tumor cells (33). CA-170 can effectively even bring unknown off-target toxicity. The interaction between
inhibit melanoma and colon cancer in rodent models, and CA-170 is PD-1 to PD-L1 is a protein-protein interaction. The contact
superior to mAbs in terms of safety (34–36). In clinical studies, CA- interfaces of PD1/PD-L1 are large, highly flat, and hydrophobic,
170 has the best effect on NSCLC and Hodgkin lymphoma with a which makes it difficult to design compounds and develop small
total clinical benefit rate of 70% and 77.8%, respectively (37). molecule inhibitors. Nevertheless, small molecule inhibitors
AUNP12 was reported by Aurigene and Pierre Fabre in 2014. It is have mature R&D pipelines, better tissue permeability, and
the first polypeptide PD-1/PD-L1 inhibitor and has a structure controllable pharmacokinetic properties, which can help to
similar to the extracellular domain of PD-1 (38). The EC50 of avoid the defects of mAbs.
peripheral blood mononuclear cells (PBMCs) proliferation rescue
experiments reached 0.41 nM (38, 39). The in vivo experiments also
showed that AUNP-12 can inhibit tumor growth and metastasis. IDO1 inhibitors
AUNP-12 can inhibit B16F10 and 4T1 tumors in rodent models, and
the tumor growth inhibition rate (TGI) of the B16F10 model reached Indoleamine 2,3-dioxygenase1 (IDO1) is a 45 kDa hemoglobin
44% (40). In 2015-2018, BMS successively published a series of oxidase and is a key enzyme in the metabolism of the L-tryptophan-
patents, and the IC50 of compounds detected by HTRF was generally kynurenine pathway. IDO1 plays an important regulatory role in the
less than 1 nM (41). In 2021, Liu et al. reported a small molecule process of immune regulation (43, 44). Functionally, IDO1 plays a
inhibitor-ZE132, of which the affinity KD was 19.36 nM. ZE132 can key role in carcinogenesis and cancer immune escape by catalyzing
specifically act on PD-L1 and has good antitumor efficacy in a variety the initial step of canine urinary ammonia pathway. IDO1 is
of syngeneic mouse models (42). overexpressed in tumor cells and antigen-presenting cells (APC). It
Small molecule inhibitors have lower binding affinity than is conducive to the formation of an immunosuppressive tumor
that of mAbs, and they are prone to off-target effects, which may microenvironment and is closely related to the poor prognosis of
TABLE 2 Summary of major marketed and clinically reported small molecule immunotherapy drugs (Up to March 2022).
Target Name Structure Company Highest Development Phases
PD-L1/VISTA CA-170 Aurigene, Curis Phase II (NCT01288911)
PD-L1 INCB-086550 Incyte Phase II (NCT04629339)
PD-L1 GS-4224 Gliead Phase 1b/2 (NCT04049617)
PD-1 MX-10181 undisclosed Maxinovel Phase I (NCT04122339)
(Continued)

Liu et al. 10.3389/fimmu.2022.961805
TABLE 2 Continued
IDO1 BMS-986205 Bristol-Myers Squibb Phase III (NCT03661320)
IDO1 INCB-024360 Incyte Phase III (NCT02752074)
STING ADU-S100 Aduro, Novartis Phase II (NCT03937141)
STING MK-1454 Merck Phase II (NCT04220866)
A2AR AZD4635 AstraZeneca Phase II (NCT04089553)
A2AR NIR178 Novartis Phase II (NCT03207867)
(Continued)

Liu et al. 10.3389/fimmu.2022.961805
TABLE 2 Continued
CXCR2 AZD5069 AstraZeneca Phase II (NCT03177187)
CXCR4 Mavorixafor X4 Pharmaceuticals Phase III (NCT03995108)
CCR2/5 BMS-813160 Bristol-Myers Squibb Phase II (NCT03184870)
TLR7 Imiquimod 3M Pharmaceuticals Marketed
TLR8 Motolimod Array Pharma, Celgene Phase I/II (NCT02431559)
ARG INCB001158 Calithera Biosciences, Incyte Phase I/II (NCT02903914)
various cancers (45). Inhibition of IDO1 can activate antitumor cisplatin in bladder cancer. In addition, there are two phase II clinical
immune responses in rodent tumor models (43). A variety of trials ongoing for bladder cancer (NCT03519256) and
IDO1 inhibitors have entered clinical studies. BMS-986205 and HNSCC (NCT03854032).
epacadostat have made the fastest progress (Table 2). BMS-986205, Developed by Incyte, epacadostat is one of the most well-
developed by BMS, is currently in phase III clinical trial studied IDO1 inhibitors. It shows good efficacy in mouse melanoma
(NCT03661320) in combination with nivolumab, gemcitabine, and models and is well-tolerated (46). However, the results of the clinical

Liu et al. 10.3389/fimmu.2022.961805
trial (NCT02752074) showed that the combination of epacadostat strategies in cancer immunotherapy has attracted widespread
and pembrolizumab in the treatment of melanoma did not meet the interest. Although small-molecule drugs targeting the
main clinical outcomes, and Incyte stopped their phase III extracellular or intracellular pathways of adaptive immunity or
trials (47). innate immunity have been developed, most of them are in the
The development of IDO1 inhibitors is not going well, and early stage of clinical trials, and more basic experiments and
some clinical trials have failed. On one hand, the reason for the clinical trials are needed to elucidate their mechanisms, clinical
failure of ECHO-301 (epacadostat plus pembrolizumab) may be efficacy, and pharmacokinetics. Nevertheless, small-molecule
that the pharmacodynamic indicators are not applicable or the inhibitors may be an effective replacement and supplement for
drug combination strategy is not matched. On the other hand, mAbs, and they will remain an important part of tumor
the reason may be that the exact regulatory mechanism of IDO1 immunotherapy in the future.
in physiology and pathology or its impact on the tumor
microenvironment are not well understood. The TDO
pathway can play a potential compensatory role after Adoptive cell therapy
epacadostat treatment, causing tumor immunosuppressive
effects (48). However, the immune-enhancing function of CAR-T
IDO1 inhibitors has been verified, and IDO1 inhibitors still
have the potential for development. In the future, the The chimeric antigen receptor (CAR) is a genetically
combination therapy of IDO1 inhibitors with other antitumor modified and synthesized chimeric antigen receptor. It is a
drugs should be further explored, which has important membrane protein composed of different protein domains in
implications for the success of clinical development. series. It is flexible and offers specific antigen recognition.
Patient-derived T cells modified by CAR in vitro can recognize
tumor antigens and exert antitumor effects without MHC
Other small molecule drugs restrictions in vivo (55).
CAR-T therapy is a revolutionary approach to cancer
Stim ulat ors of inte rfe ron gene s (STING) is an therapy. CAR-T therapy has made breakthroughs in
immunostimulatory target and an important adaptor protein lymphomas, mainly targeting CD19. In 2017, the FDA
anchored in the endoplasmic reticulum that senses foreign DNA approved two CAR-T products targeting CD19 (Kymriah
invasion. Now the STING signaling pathway has become a new and Yescarta, Table 3) (56, 57). The first generation of CAR
target for cancer and autoimmune diseases. Experiments have contains CD3x, and the second generation adds a
shown that the activation of STING pathway can induce costimulatory domain CD28 or 4-1BB based on CD3x.
antitumor effects. A variety of drugs such as ADU-S100 are Through March 2022, the FDA has approved five CAR-T
under clinical studies (Table 2) (49, 50). The clinical application products, all of which are second-generation CARs with
of STING agonists is mainly focused on intratumoral injections, indications focused on lymphoma (58, 59). The third-
and it is unclear whether systemic administration is safe. generation CAR uses lentivirus as a transfection vector, and
In addition, inhibitors of A2A adenosine receptor (A2AR), the intracellular segment of the CAR can have two or more
chemokine receptors, toll-like receptors (TLRs), arginase 1 costimulatory signals. However, some studies have shown that
(ARG), and other targets are in clinical development and are the killing activity of the third-generation CAR-T cells is not
expected to provide more choices for antitumor drugs (Table 2) significantly improved. This may be because the activation
(51–54). Many projects have entered phase II/III clinical trials. signal generated by one co-stimulatory molecule of ITAM
Polypeptide inhibitors, which can combine the already reaches the threshold of T lymphocyte activation
characteristics of antibodies and small-molecule drugs, are signal. Simply increasing the number of ITAM will not
important directions for the development of inhibitors. On further enhance the activation effect of CAR-T.
one hand, they have similar affinity and specificity as New ideas for CAR design are now emerging to improve
antibodies. On the other hand, they have good tissue efficacy. Dual-target CAR-T cells can independently identify
penetration and provide tunable pharmacokinetic half-life and target antigens and address the off-target effect. CD19/CD22
renal clearance route to avoid hepatic and gastrointestinal CAR-T and CD123/CLL1 CAR-T have shown significant
toxicities due to their small molecular weight. antitumor activity and are currently in clinical studies, some of
Small molecules are agents with a low molecular weight that which have entered phase II/III (Table 3) (60, 61). According to
are capable of modulation of intracellular targets. And small EXUMA Biotech, targeting CD3 T cells by subcutaneous
molecules are promised to improve the therapeutic management injection of a self-inactivating lentiviral vector encoding a
of solid tumors due to their easy administration, high CAR targeting CD19 resulted in the successful generation of
bioavailability, and favorable safety profile. Given these corresponding CAR-T cells in vivo and showed significant effects
characteristics, the development of small molecule-based in mice (AACR 2022 Abstract #3294/11). This provides a new

Liu et al. 10.3389/fimmu.2022.961805
TABLE 3 Summary of major marketed and clinically reported adoptive cell therapy (Up to March 2022).
Category Target Name Company Highest Development Phases
CAR-T CD19 Kymriah Novartis Marketed

CAR-T CD19 Yescarta Gliead Marketed
CAR-T CD19 Tecartus Gliead Marketed
CAR-T CD19 Breyanzi BMS Marketed
CAR-T BCMA Abecma Bluebrid Bio Marketed
& BMS
CAR-T BCMA bb21217 Bluebrid Bio Phase I (NCT03274219)
CAR-T CLDN6 BNT211 BioNtech Phase I/IIa (NCT04503278)
TCR-T NY-ESO-1 NY-ESO-1 TCR Adaptimmune Therapeutics Phase I/II (NCT05296564)
TCR-T PRAME MDG1011 MediGene AG Phase II (NCT03503968)
TILs – LN-144 Iovance Biotherapeutics Phase II (NCT03645928)
TILs – LN-145 Iovance Biotherapeutics Phase II (NCT04614103)
CAR-NK CD19 FT596 Fate Therapeutics Phase I (NCT04245722)
CAR-NK NKG2D NKX101 Nkarta Therapeutics Phase I (NCT04623944)
CAR-NK CD7 anti-CD7 CAR-pNK PersonGen BioTherapeutics Phase I/II (NCT02742727)
CAR-NK CD33 anti-CD33 CAR-NK PersonGen BioTherapeutics Phase I/II (NCT02944162)
opportunity to overcome the challenges of production time, transduction methodologies, and allogeneic CAR-T are bound
scale, and cost of adoptive cell therapies. to lead to improved responses and transform the treatment of
For solid tumors, Hegde et al. constructed TanCAR-T that patients with cancer.
could enhance T cell function and reduce antigen escape by
facilitating crosstalk between HER2-ScFv and IL-13Ra2, thus
increasing CD28 expression. The data of TanCAR-T showed TCR-T
good efficacy in a mouse glioblastoma model (62). In 2022,
Grosskopf et al. published a delivery method for hydrogel that Various new methods have been developed to enhance the
can improve the efficacy of treatment of solid tumors by antitumor efficacy of immune system, including targeting new
injection into areas near the tumor (63). BioNTech announced antigens, using new engineering or modifying TCR, and creating
the results of the first human clinical trial (NCT04503278) of safety switches for internal suicide genes. By transferring the
BNT211—a new generation of CAR-T therapy targeting solid exogenous TCR gene that specifically recognizes TAAs into T
tumors. The combination of CAR-T targeting CLDN6 and cells, TCR-T can be constructed to improve the affinity to TAAs
mRNA vaccine CARVac for CLDN6 can effectively enhance and exert an MHC-dependent antitumor effect (65). Compared
the efficacy and provide new ideas for the treatment of solid with CAR-T therapy, TCR-T therapy has a better safety profile
tumors (AACR 2022, Abstract #CT002). In addition, due to its MHC restriction, which can alleviate adverse reactions
combination therapy with immune checkpoint inhibitors may such as cytokine storms. The TCR-T category currently in
also enhance the efficacy of CAR-T for solid tumors (64). clinical trials is mainly targeting NY-ESO-1. NY-ESO-1 TCR
However, there are several limitations to the application of produced by Adaptimmune Therapeutics is currently in phase I/
this technology. Firstly, the expression of CAR mediated by II clinical trials (Table 3).
retroviral or lentiviral vectors may have an impact on the gene MART TCR-T, gp100 TCR-T, and TCR-T targeting MAGE-
expression of T cells, which may produce unpredictable results. A3 or MAGE-A4 have achieved positive results in clinical trials.
So, a comprehensive safety assessment of CAR-T cells is required However, safe use in the clinic should consider the type of
before application. Secondly, the proliferation of CAR-T cells antigen and TCR affinity (66, 67). In a clinical trial of nine
can only be achieved after induction and activation. Therefore, patients treated with TCR-T, 56% (5/9) of patients experienced
whether the large-scale expansion of T cells in vitro can maintain an OR, one of which was a CR. However, three of nine (44%)
immune activity is an important factor. Thirdly, necessary patients experienced severe neurologic toxicities, including two
technical processes are required for different patients, which deaths. The cause of death, in part, may be a cross-reaction of
may take high costs and long periods. In addition, TCR-T with a similar epitope of MAGE-A12 in brain.
immunosuppressive TME and efficiency of delivery to the While targeting NY-ESO-1, MAGEA3, and other TAAs is an
tumor site are also major barriers to a successful CAR-T attractive strategy for the application of ACT for the treatment of
therapy. In the future, innovations in CAR design, solid cancers, caution must be taken to ensure a lack of cross-

Liu et al. 10.3389/fimmu.2022.961805
reactivity with vital normal tissues. In addition, modification of However, several issues have emerged that need to be
the CDR region of TCR must be performed with caution. addressed. Firstly, there is an urgent need to identify
Because the modified receptors, similar to those produced after alternative and predictive biomarkers to better select
immunization in HLA-transgenic mice, are not negatively appropriate patients for TILs treatment to improve response
selected in the thymus and may be potentially reactive to rates and duration. Secondly, TILs are needed to be improved
unrelated normal host proteins. There is a need to develop memory and effector characteristics for longer persistence and
better screening methods to avoid such toxicity in the future. As enhanced antitumor activity. In addition, although TCR-T and
more antigen-specific TCRs are identified, more data will CAR-T therapies show very competitive performance, they can
become available to better understand how to use TCR-T to only target a single TAA or a limited array of TAAs. By contrast,
treat patients. Immunosuppressive TME also limits the efficacy TILs can recognize a panoply of unknown TAAs, which
of TCR-T therapy. Combination therapy targeting TME may be ultimately demonstrates that TILs therapy has a bright future,
a potential strategy to improve the efficacy of TCR- especially with approaches that promote TAA release and
T immunotherapy. enhance T-cell persistence. At last, we also need more
investigations on combination approaches that can improve
long-term efficacies and reduce the cost to a more
TILs affordable level.
Tumor-infiltrating lymphocytes (TILs) are immune cells

that exist in tumor tissues and can specifically respond to CAR-NK
TAAs. Using TILs is an effective treatment for many cancers.
The first clinical pilot study using TILs was reported in 1988 for NK cells play an important role in innate immunity. CAR-
metastatic melanoma. The result demonstrated partial response NK is a therapy like CAR-T, which uses CAR to modify NK cells.
in 2 patients and partial regression in 1 patient. Tumor-specific CAR-NK can be activated by targeting TAAs to release cytotoxic
cytolytic activity was observed in 5 patients (68). In another cytokines such as granzyme to kill tumor cells (76). CAR-NK is
study by Rosenberg et al., three sequential clinical trials about currently still in preclinical or clinical research, which mainly
TILs were performed. Objective response rates in the three trials targets CD19, NKG2D, CD7, or CD33, etc. (Table 3).
were 49%, 52%, and 72%, respectively. A study showed that 22% In a phase I/IIa clinical trial, 11 patients with non-Hodgkin’s
of all patients achieved complete tumor regression and 19% of lymphoma and chronic lymphocytic leukemia were treated with
the patients were disease-free for more than three years (69). The CD19 CAR-NK. And seven patients experienced CR without
OR from patients treated with standard TILs is greater than 50% serious adverse reactions (77). In 2020, NEJM published a CAR-
and many of these patients experiencing durable CRs beyond 5 NK treatment for hematologic tumors using cord blood-derived
years (70–72). The effort to extend TIL therapy for the treatment CAR-NK targeting CD19 that achieved complete remission in
of other solid cancers is ongoing. Galon et al. studied TILs in seven patients, all without a cytokine storm or neurotoxic
patients with colorectal cancer by gene expression profiling and response. Moreover, one year after treatment, CAR-NK cells
in situ immunohistochemical staining (73). The results are still present in the patient’s body, which is especially
suggested that TILs act as a valuable prognostic tool in the important for long-term antitumor therapy (77). NKG2D is an
prediction of patient survival, and the results gave convincing activating receptor of NK cells, which is involved in the
information regarding tumor recurrence and survival in patients recognition of virus-infected cells and the killing of tumor
with early-stage colorectal cancer. cells. In a phase I clinical trial of NKX101 (allogeneic CAR-
TILs therapy mainly works by isolating TILs from tumor NK cells targeting NKG2D), 3 of 5 patients treated with high
tissues, amplifying them in vitro with high doses of IL-2, and doses (1.5 billion×3 and 1 billion×3) achieved CR without
then injecting them into patients (68, 74). Iovance’s LN-144 serious adverse reactions (NCT04623944). At AACR 2022,
therapy has achieved a disease control rate (DCR) of 80% and Senti Bio announced the results of a preclinical study of CAR-
ORR of 38% for stage IIIc/IV melanoma patients (Table 3). More NK with a genetic circuit that secretes IL-15 in a controlled
notably, patients who are not responding to immune checkpoint manner to improve efficacy in the treatment of solid tumors
inhibitors still benefit. Multiple clinical trials of TILs for various (AACR 2022 Abstract #584).
types of solid tumors are currently ongoing, thus showing Compared with CAR-T, CAR-NK usually produces IFN-g
therapeutic potential for malignancies such as melanoma, and GM-CSF, thus it is less likely to produce cytokine storm.
lung, and colorectal cancers (75). TILs therapy is separate CAR-NK is widely available and can be derived from allogeneic
from natural lymphocytes isolated from tumor tissues and it delivery without need of HLA matching. However, some factors
can recognize a variety of different targets with no cytokine limit the wide use of CAR-NK. The manufacturing process of
storms reported. Thus, TILs therapy is safer than TCR-T and CAR-NK can be further simplified and optimized. Current
CAR-T therapies and more effective in solid tumors. CARs are designed for CAR-T and they are not the best for

Liu et al. 10.3389/fimmu.2022.961805
application to NK cells. CAR design for optimal NK cell techniques to enhance the antitumor effects of OV therapy
activation and cytotoxicity needs to be improved. Secondly, including replacing some viral genes with oncogenes or
CAR-NK’s unspecific killing function needs to be combined integrating TAAs genes into the OV genome to promote the
with CAR-derived specific killing. In addition, limited production of specific immune responses (85). In addition, the
proliferation and inhibition of the tumor microenvironment combination with immune checkpoint therapy has also become
limit the clinical development of CAR-NK (78). an important research direction. The clinical results of CG
The lack of in vivo durability of infused cells in the absence of Oncology’s OV therapy CG0070 in combination with
cytokine is one of the major drawbacks of CAR-NK therapy. Keytruda show 89% CR (AACR 2022 Abstract#CT036) (86).
Modified CAR-NK which can secret IL-2/IL-15 has demonstrated OV therapy is efficacious and safe, and it is a very promising
good results in some preclinical research (79). In addition, the tool for tumor immunotherapy (87–89). However, its mode of
induction of a memory-like phenotype of CAR-NKs with a cocktail administration is currently limited to intra-tumoral injection,
of cytokines (IL-12, IL-15, and IL-18) resulted in improved which has limitations in clinical use. Intratumoral
responses to B-cell lymphomas in vitro and in vivo (80, 81). administration is expensive and difficult, especially in cases of
Immunosuppressive TME and efficiency of delivery to tumor site malignant gliomas. Some of the novel approaches involve the use
are also major barriers to successful CAR-NK therapy. With more of nanoparticles, complex viral particle ligands, and immuno-
pre- and clinical data in further, CAR-NK therapy may lead to modulatory agents to deliver the virus into tumor. Alternatively,
revolutionary advances in tumor immunotherapy. In addition, delivery of OV via nanoparticles using a technologically complex
combined therapy which includes immune checkpoints blockade image-guided delivery system has also been considered (90).. In
and targeted therapy may provide a new direction for CAR-NK- the future, OV therapy is expected to make exciting progress by
based immunotherapy. solving the problem of drug delivery and combining with other
immunotherapy methods
Oncolytic virus
Cancer vaccines
Oncolytic viruses (OV) therapy is a new type of antitumor
therapy, which can target tumor cells and replicate in cells to kill Preventive cancer vaccines
tumor cells. OV has become the forefront of tumor biotherapy
and it is increasingly common. OV can be obtained through The immunoprevention of cancer and cancer recurrence has
natural or genetic engineering, mainly including herpes virus, received extensive attention; preventative cancer vaccines have
adenovirus, and pox virus (82). OV exerts its antitumor effects made more progress in preventing cancer than in eliminating
mainly by selectively replicating within tumor cells and established cancer. Nevertheless, preventing tumors obviously
eventually leads to tumor cell lysis. The release of TAAs after impacts survival. Preventive cancer vaccines mainly refer to
lysis can activate the immune system to eliminate tumor cells. vaccines against viruses with high carcinogenic relevance.
The release of cytokines by tumor cells infected with OV can HBV and HPV vaccines are the main representatives. The
eliminate metastatic tumor cells (83, 84). In 2015, AMGEN’s T- pathogenesis of HBV-associated hepatocellular carcinoma is
VEC became the first OV therapy on the market with an well supported by the literature (91, 92). A variety of new
indication of melanoma, thus marking the maturity of this HBV vaccines are now on market, such as Hepacare,
technology (Table 4). Researchers are currently using various HEPLISAV-B, and PreHevbrio, which expand the efficiency
TABLE 4 Summary of marketed and clinically reported oncolytic virus (Up to April 2022).
Virus Name Company Highest Development Phases
HSV-1 T-VEC AMGEN Marketed (FDA)

ECHO-7 RIGVIR LATIMA Marketed (Latvia)
Adenovirus H101 Sunway Marketed (NMPA)
HSV-1 DELYTACT Daiichi-Sankyo Marketed (MHLW)
Adenovirus CG0070 CG Ocology Phase III (NCT04452591)
Adenovirus Reolysin Oncolytics Biotech Phase II (NCT04445844)
Adenovirus DNX-2401 DNAtrix Phase II (NCT02798406)
Coxsackievirus Cavatak Merck Phase II (NCT04152863)
HSV-1 G207 Treovir Phase I/II (NCT00028158)
Poliovirus PVSRIPO Tocagen Orphan Drug (Glioma; Glioblastoma)

Liu et al. 10.3389/fimmu.2022.961805
and scope of protection. HPV vaccines mainly include bivalent DC vaccines suffer from limited cell sources, long preparation
(Cervarix), quadrivalent (Gardasil), and nine-valent (Gardasil9), periods, and high costs. However, their advantages include low
thus focusing on the protection of subtypes 16 and 18 used to side effects, good tolerance, and long-term immunological
prevent cervical cancer, vaginal cancer, and vulvar cancer caused memory, which still give them broad market prospects.
by HPV. Due to the complex pathogenesis of tumors, this The key to the development of the cancer vaccine is the need
method can only be used as an auxiliary preventive method. to identify the appropriate biomarkers and optimize the
This type of vaccine can only be used to prevent viral infection— combination of treatments to improve their effectiveness in
not tumorigenesis. patients. The research on vaccines has been advancing in the
past few decades, and many different characterized cancer
vaccines are now available. However, there are still some
Therapeutic cancer vaccines problems that must be solved, including suitable tumor antigen
and adjuvant components, suitable delivery modes, and effective
A better understanding of the breadth of TAAs, the methods to overcome immune attack. Although neoantigens are
development of natural immune response, and new antigen the best option for antitumor immunotherapy, the problem of
delivery technologies will help to improve vaccine design. obtaining individualized neoantigens hinders the application of
Current mature therapeutic vaccines include dendritic cell cancer vaccines. This is mainly due to inherent alterations in
(DC) vaccine, which has antitumor effects by inducing the tumor cells and the formation of an immunosuppressive TIME.
patient’s monocytes to become DCs ex vivo by TAAs Several approaches have been developed to overcome difficulties,
stimulation. The cells are then infused back into the patient to including the use of immunostimulatory adjuvants, in
stimulate the activation and expansion of cytotoxic T combination with ACT and ICB.
lymphocytes (CTLs). DC vaccine can offer long-term immune
memory and can prevent tumor recurrence. Provenge is the first
DC vaccine approved by the FDA for castrate-resistant prostate Mechanisms in cancer
cancer (Table 5). The DC vaccine Ilixadencel was granted immunotherapy resistance
orphan drug status by the FDA in 2021 for the treatment of
patients with soft tissue sarcoma. Aivita Biomedical’s DC Cancer immunotherapies, such as immune checkpoint
vaccine AV-GBM-1 clinical trial (NCT03400917) results show blockade (ICB) and adoptive cell therapies (ACT), are effective
a 28% increase in 15-month OS for glioblastoma patients. With for patients with various cancers (98). However, the response
the development of sequencing technology and bioinformatics, rate of cancer immunotherapies is still limited due to the lack of
more and more tumor antigens have been discovered and can be immunogenic antigens and various immune-resistant
used to distinguish tumor cells from normal cells. A personalized mechanisms (99). Understanding the immune resistance
vaccine designed in this way is an important development mechanisms is essential to improve the efficacy of current
direction for cancer vaccines in the future (93). Multiple cancer immunotherapies.
studies are reporting that personalized vaccines have good
efficacy in the treatment of melanoma (94, 95). A combination
with immune checkpoints is also an important research Primary resistance and
direction and can show better efficacy than a single vaccine adaptive resistance
therapy (96). In addition to DC vaccines, therapeutic vaccines
include tumor cell vaccines, DNA/mRNA vaccines, and peptide Patients who have primary resistance to cancer
vaccines (97). immunotherapies do not respond to the initial therapy.
TABLE 5 Research progress of therapeutic cancer vaccines (Up to April 2022).
Name Company Highest Development Phases
Provenge Dendreon Marketed (FDA)

Cimavax-EGF Bioven Marketed (Cuba)
Mutanome BioNTech Phase I (NCT04183166)
NEO-PV-01 Neon Therapeutics Phase I (NCT02897765)
AV-GBM-1 Aivita Biomedical Phase II (NCT03400917)
TEDOPI OSE Immunotherapeutics Orphan Drug (HLA-A2 NSCLC)
Bristol-Myers Squibb
Ilixadencel Immunicum Orphan Drug (Soft tissue sarcoma)

Liu et al. 10.3389/fimmu.2022.961805
Adaptive resistance refers to the mechanism by which tumor mitochondrial activity to decrease the production of reactive
cells can be recognized by the immune system, but it can adapt oxygen species (ROSs) for survival (Warburg effect) (111).
to immune attack to protect itself as the tumor progresses. The Enhanced glycolysis in melanoma cells is associated with
mechanism of adaptive resistance may include primary reduced infiltration of CD8+ T cells in tumors and resistance
resistance, and the mechanism of primary resistance may also to in vitro T cell lysis and in vivo pericyte therapy, partially due
be the result of adaptive resistance. to increased production of immunosuppressive lactate (112).
The most fundamental reason why tumor cells cannot be In addition, tumor cell-extrinsic mechanisms that lead to
recognized by T cells and thus lead to non-response to primary and adaptive resistance involve components other than
immunotherapy is the lack of tumor antigens. In addition, tumor cells within TIME. Tregs reduce the expression of MHC-
cancer cells may have tumor antigens, but the change in the II molecules by secreting the inhibitory cytokine IL-10, which
antigen presentation mechanism can also result in the can affect DC maturation and suppress immune responses (113).
occurrence of immune resistance (100). MDSCs can express CD11b and CD33 to promote blood vessel
In tumor cell-intrinsic factors, insufficient tumor growth, tumor invasion, and metastasis. CXCR2 can induce
antigenicity and neoantigens contribute to primary and MDSCs to infiltrate tumors and mediate immune resistance
adaptive resistance. Tumor cells can evade specific immune (114). Tumor-associated macrophages (TAMs) can also affect
recognition by T cells by downregulating the expression of immunotherapy responses. Several reports have discussed the
TAAs, TSAs, and surface MHC. Tumor cells with relatively role of macrophages in mediating therapeutic resistance in
weak immunogenicity can escape the surveillance of the immune cancer (115–117).
system and selectively proliferate. After the immune selection
process, the immunogenicity of the tumor is getting weaker and
weaker. The emergence of neoantigens can inhibit tumor Acquired resistance
progression, whereas poorly immunogenic tumors lack
response to PD-1/PD-L1 blockade. Deletion of neoantigens is A hallmark of cancer immunotherapy has been the
responsible for primary resistance to immunotherapy in triple- induction of long-lasting tumor responses. However, patients
negative breast cancer (TNBC) (101). LINK-A, a lncRNA that who once responded to ICB sometimes relapse due to acquired
can degrade phospholipase C by ubiquitin ligases, has a negative resistance. Schachter et al. showed that 1/4 to 1/3 of patients with
correlation with cytotoxic T lymphocytes infiltration in TNBC metastatic melanoma who received anti-PD-1 or anti-CTLA-4
(102). It is currently believed that the higher the tumor mutation therapy relapsed after ongoing treatment, even if they were
burden (TMB), the more neoantigens are produced, and the effective against immunotherapy (118). The possible
stronger T cell response are. Clinically, melanoma, renal cell mechanisms of acquired resistance mainly include B2M
carcinoma, and NSCLC with high TMB have a better response to mutation and loss of HLA heterozygosity, changes in tumor
anti-PD-1 therapy, while pancreatic cancer and prostate cancer target antigens, and up-regulation of alternative immune
with low TMB are less effective (103, 104). checkpoints. There is evidence for each of these mechanisms
In tumor cell-intrinsic factors, tumor signaling pathways can can lead to acquired resistance to ICB or ACT.
produce immunosuppressive components, or alter some gene B2M plays an important role in MHC-I antigen-presenting,
expression to affect the efficacy of ICB. Oncogenic signaling antigen recognition, and T cell infiltration (119). Mutated B2M
through the MAPK pathway results in the production of VEGF gene affects normal folding and transport of MHC-I, resulting in
and IL-8, which have inhibitory effects on T cell recruitment and resistance to ICB (120). Sade-Feldman et al. analyzed post-
function (105). Activation of AKT signaling through PTEN loss treatment biopsy specimens from 17 metastatic melanoma
was also correlated with reduced CD8+ T cells in tumors and a patients with ICB treated, and they found the percentage of
poor response to anti-PD-1 in melanoma patients (106). IFN-g heterozygous deletions and point mutations of B2M was 9.4%,
signaling pathway in TIME activates JAK-STAT signaling, which suggested that B2M loss may be a common mechanism of
which can induce PD-L1 expression (107). Wnt/b-catenin resistance to targeted CTLA-4 or PD-1 therapy (121). GAO et al.
signaling pathway is closely related to the occurrence and showed that mutations in Janus kinase 1 (JAK1), JAK2, and B2M
development of various tumors (108). Studies have shown that in tumor samples after immunotherapy may be the mechanisms
Wnt/b-catenin signaling in melanoma cells can prevent of acquired resistance to anti-PD-L1 therapy in melanoma
antitumor responses by interfering with the recruitment of patients (122).
BATF3-expressing DCs (109, 110). Additional evidence of loss of antigen-presenting machinery
In tumor-intrinsic factors, immunosuppressive metabolism leading to acquired resistance to cancer immunotherapy is
in TIME can suppress immune response. Various metabolisms provided by a case of a patient with metastatic colorectal
in tumor may cause immune resistance. Tumor cells carcinoma who responded to TILs ACT. The TILs recognized
preferentially utilize glycolysis to produce ATPs and molecules mutated KRAS G12D presented by HLA-C*08:02 resulting in an
necessary for cell division such as nucleic acids, while reducing objective antitumor response, followed by an isolated relapse in a

Liu et al. 10.3389/fimmu.2022.961805
lesion that had lost HLA-C*08:02 in chromosome 6 (123). Combination of different ICBs
Therefore, acquired resistance to ICB and ACT could be
mediated through genetic mechanisms that altered antigen- An example of enhanced efficacy with combination therapy
presenting machinery and IFN-g signaling. is the use of anti-CTLA-4 and anti-PD-1, which results in
Cytotoxicity T cells are specific for cancer cells that express higher response rates and improved survival in melanoma
their cognate antigen, but cancer cells may develop acquired patients (130, 131). In the phase III trial in patients with
resistance through decreased expression or mutations in these unresectable or metastatic melanoma, the five-year survival
antigens. T cells turned on by checkpoint blockade therapy rate of the combination group (nivolumab plus ipilimumab)
primarily recognize mutational neoantigens (104, 124). Gene reached 52%, and the five-year survival rate of the nivolumab
deletions, mutations, or epigenetic alterations can lead to a group and ipilimumab group was 44% and 26% respectively
decrease in MHC-presented mutational neoantigens and (131, 132).
acquired resistance. One study found that the main cause of In addition, blockades of TIM-3, LAG-3, and TIGIT
resistance to CD19 CAR-T cells for acute lymphoblastic are receiving increasing attention. In the treatment of
leukemia was the loss of target antigens, which is mainly hepatocellular carcinoma, it was found that blocking both
caused by antigen escape and lineage conversion (125, 126). TIM-3 and PD-1 can completely reverse the exhausted state
After immune checkpoint treatment, due to compensatory of T cells and has a significant antitumor effect. However,
effects, the expression of other immune checkpoints is elevated, blocking TIM-3 or PD-1 alone only partially restored the
which in turn causes acquired resistance. TIM-3 is a negative function of T cells (133). Both LAG3 and PD-1 can transmit
immune checkpoint. It was found that TIM-3 was highly co-inhibitory signals and blocking both LAG3 and PD-1 can
expressed in T-cells from animals that were resistant to anti- play an immune synergistic effect by enhancing CD8+ T cell
PD-1 treatment, which confirmed that the main mechanism of function and clearing Treg (134). TIGIT is mainly expressed
resistance to anti-PD-1 immunotherapy is the selective on activated T cells and NK cells, which mediates
activation of a new immune checkpoint (23). In addition to immunosuppressive signal. TIGIT blockade synergizes with
TIM-3, other known alternative immune checkpoints are LAG- anti-PD-1 can enhance CD8+ T cell function and promote
3, TIGIT, and VISTA, etc. Several clinical trials are currently tumor regression (135).
undergoing to test antibodies against these immune checkpoints,
both as monotherapy and combination therapy strategies, to
provide additional clinical benefits (127).
Great advances occurred in the field of cancer immunotherapy Combination with chemotherapy
due to years of mechanism exploration and clinical application and radiotherapy
development. However, to date, the benefits have been limited to a
small number of patients with certain cancer types. In addition, Previously, it was believed that chemotherapy could lead to
thanks to more successful immunotherapy treatments, we now have immunosuppression by affecting the number or function of
a large proportion of patients who initially respond but eventually lymphocytes. But in-depth studies have found that some
relapse. The mechanisms of immunotherapy resistance are chemotherapies can enhance tumor immunogenicity (136).
complicated, and we are likely just observing the tip of the Some studies believe that chemotherapy can enhance the
iceberg. To bring clinical benefit to the majority of patients, we antitumor immune response, among which pembrolizumab
need to have a comprehensive understanding of the tumor cell- combined with chemotherapy has been approved by the FDA.
intrinsic and -extrinsic factors that lead to immunotherapy Liposome doxorubicin combined with immunotherapy
resistance. These mechanisms can lead to primary, adaptive, and produces synergistic antitumor effects in mice, and more mice
acquired resistance to immunotherapy. Elucidating these achieve complete tumor remission and prolonged survival (137).
mechanisms will provide important clues to overcome resistance High-frequency and low-dose chemotherapy can effectively
to immunotherapy. activate CTLs and inhibit immunosuppressive cells in TIME,
which can promote efficacy and solve the problem of immune
resistance (138). In an in-situ CRC-bearing mouse model with
ineffective anti-PD-L1 treatment, the proportion of TILs was
Combination strategies for significantly increased after combination with oxaliplatin. At the
cancer immunotherapy same time, the combination of oxaliplatin and a novel PD-L1
blocker (PD-L1 Trap) significantly prolonged the survival of
To enhance the effectiveness of cancer immunotherapy and tumor-bearing mice (139). Chemotherapy combined with anti-
overcome immunotherapy resistance, combination therapy has PD-1 is used as a first-line treatment for advanced NSCLC,
become a hot topic of current research (128, 129). Currently, ICB which has significantly more clinical benefits than a single
is the most used cancer immunotherapy in clinical combination. agent (140).

Liu et al. 10.3389/fimmu.2022.961805
Radiotherapy promotes the release of TAAs, TSAs, or Other combination immunotherapies

damage associated molecular pattern molecules (DAMPs),
which can enhance the immunogenicity of tumor cells and The functional inhibition of CAR-T by PD-1/PD-L1 has
promote the recruitment and infiltration of immune cells. This been well established, which also provides the basis for the
relationship is the rationale for combination with combination of PD-1/PD-L1 blockade and CAR-T. Existing
immunotherapies. In a study of mouse model, radiotherapy preclinical studies have shown that CAR-T cells plus PD-1/
combined with anti-PD-1 treatment reversed immune PD-L1 blockade can effectively enhance the antitumor effect
resistance (141). In the treatment of metastatic melanoma, (152, 153).
radiotherapy combined with anti-CTLA-4 and anti-PD-1 IDO1 inhibitors have been in active clinical investigation
therapy may become a new idea in combined and preliminary results suggest that IDO1 inhibitors produce
immunotherapies (142). Pilones et al. reported that anti- additive efficacy when combined with cancer immunotherapies
CTLA-4 combined with radiotherapy effectively inhibited the despite low activity as a single agent. Results from a phase I/II
lung metastasis of breast cancer in a mouse model (143). Deselm clinical trial, which combined IDO1 inhibitor epacadostat and
et al. found that radiotherapy made it more effective for CAR-T Ipilimumab for the treatment of metastatic melanoma, showed
cells in a mouse model of pancreatic cancer, and the tumor cells an objective response and no tumor progression in some
that did not express the CAR target were also killed by CAR-T patients (154). In addition, IDO1 inhibitors combined with
cells (144). ICBs are also tested in various clinical trials (NCT03519256,
NCT03854032, and NCT03661320). Combinations of type I
interferons, TLR inhibitors, or STING agonists have also
Combination with targeted therapy shown promise in preclinical models (155–157).
T-VEC can selectively replicate within tumors and produce
Targeting intracellular signaling pathways with small granulocyte-macrophage colony-stimulating factor (GM-CSF),
molecule inhibitors is effective in rapidly reducing tumor which triggers DC differentiation and enhancement of antigen
volume. However, many of these drugs do not have durable presentation. This makes OVs susceptible to immunotherapy.
effects, mainly due to the emergence of other compensatory OV therapy CG0070 in combination with Keytruda showed 89%
pathways (145, 146). Emerging strategies to enhance CR in a clinical trial (AACR 2022 Abstract#CT036) (86).
immunotherapy response are being developed based on novel Current combined strategies are complex because the
insights into T cells and overall immune function. potential combination approaches far exceed the available
Pembrolizumab combined with BRAF inhibitors shows human and technical resources. There is an urgent need for us
synergistic antitumor activity and prolongs response time in to test these combinations in appropriate preclinical models and
mice with metastatic melanoma (147). to accelerate clinical translation through novel approaches to
Tumor angiogenesis has an important relationship with clinical trial design.
tumor immunity. VEGF is related to the generation and
regulation of MDSCs, so anti-angiogenic therapy combined
with immunotherapy has a synergistic effect. Preclinical studies Discussion
have shown that the combination of VEGFR inhibitor Axitinib
and anti-CTLA-4 can enhance the antigen-presenting ability of Cancer occurrence and development is a complex process.
DC to promote T cell proliferation in a mouse melanoma Various immune-evasion mechanisms can counteract the body’s
model (148). Data from clinical trials with the combination of immune response, which becomes more complex as cancer
ipilimumab and VEGF inhibitor bevacizumab showed that progresses. Cancer immunotherapy can kill and eliminate
more than 30% of patients in the combination group tumor cells through the immune system, thus becoming
observed a significant increase in CCR7+ CD8+ T cells, another revolutionary treatment after surgical resection,
compared to only 6% of patients in the ipilimumab group radiotherapy, chemotherapy, and targeted therapy.
(149). Studies have shown that sunitinib can reverse tumor- Various cancer immunotherapies have shown promising
induced immunosuppression by reducing MDSCs (150). clinical efficacy. However, cancer immunotherapy still faces
Various targeted therapies, such as EGFR, ALK, ROS1, and many problems and challenges. MAbs therapy is a very
MEK inhibitors, are being clinically tested in combination promising treatment for immunotherapy, which has been
with ICBs. repeatedly demonstrated in clinical use. However, due to the
ACT combined with targeted therapy is also an innovative immunogenicity, mAbs can cause irAEs, which requires strict
immunotherapeutic approach. Li et al. combine CAIX-specific monitoring in clinical use. The production process of mAbs is
CAR-T cells and sunitinib, which induces a potent antitumor time-consuming and costly, and new purification strategies are
response in an experimental model of metastatic RCC (151). needed for higher purity of mAbs. These problems are

Liu et al. 10.3389/fimmu.2022.961805
determined by the nature of the antibody itself, and we believe molecule immunomodulator targeting immunosuppressive
these problems will partly be solved with new design strategies TIME may be effective for solid tumors.
and further optimization. The overall immune response rate of The major challenge in oncolytic virus therapy is the
patients treated with ICB is not high, and there is a need to find targeted delivery of the virus into the tumor. In most cases,
reliable and effective biomarkers for precise and personalized systemic administration does not work well because of
immunotherapy. In combination with chemotherapy, mAbs preexisting immunity. Some novel approaches involve the use
have generated success against advanced-stage cancers, which of nanoparticles, complex viral particle ligands, and immuno-
previously had poor outcomes. In addition, combinations with modulatory agents to deliver OVs into the tumor. Alternatively,
different mAbs also showed a strong anti-tumor effect. delivery of OVs via a nanoparticles using technologically
Combination therapy may provide new opportunities for complex image-guided delivery system has also been
mAbs to reduce the side effects and improve the therapeutic considered (90). Immune response after OVs infection
effect in the future. Conjugation of cytotoxic agents to mAb suppresses the replication of the virus thereby posing a
allows for specific delivery of payloads to tumors, while hindrance to the effective functioning of OVs therapy.
multispecific antibodies grant novel mechanisms that increase Therefore, increasing anticancer treatments and consequently
specificity and facilitate delivery to historically intractable patient prognosis through contributions from molecular
compartments. Besides, Fc- engineering mAbs can endow biology, immunology, genomics, and bioinformatics will
mAbs with stronger antitumor and immune activation ability provide a strong foundation for OVs’ potential clinical success
through the incorporation of amino acid and glycan changes. in the future.
With an increased understanding of immunobiology and the For preventive cancer vaccines, the successes of Gardasil are
continued development of molecular biological methods, the exciting. The next step is perhaps to look for other important
possibilities for mAbs therapy are bounded only by the scope of tumorigenic antigens, possibly other viruses, to expand
human ingenuity. protection for people. In addition, for therapeutic cancer
Small molecule inhibitors for cancer immunotherapy always vaccines, an improved antitumor immune response is still in
occupy an important position, although the sales of mAbs are far high demand because of the unsatisfactory clinical performance
ahead. Small molecule inhibitors have mature R&D pipelines of the vaccine in tumor inhibition and regression. Personalized
and the production process of small molecule inhibitors is more vaccine design and appropriate combined therapy could
controllable than mAbs, which can help reduce costs. The represent the best approach to increase the efficacy of
controllable pharmacokinetic properties can help reduce the cancer vaccines.
impact of side effects, and the good tissue permeability makes Compared with traditional chemoradiotherapy and targeted
small molecule inhibitors useful for solid tumor therapy, immunotherapy has significant advantages. Under the
immunotherapy. Small molecule inhibitors will always be an in-depth study of anti-tumor immune response mechanism,
effective replacement and supplement for mAbs. Currently, a great progress has been made in the field of tumor
new form of small molecule inhibitor, proteolysis targeting immunotherapy. With the widespread application of
chimeras (PROTAC) is tested in (pre-)clinical, such as IDO1 immunotherapy, the occurrence of immune resistance has
PROTACs. But many issues need to be addressed especially on become an unavoidable problem. We are still at a very early
whether it is a safe approach or whether there is a saturation in stage of understanding the mechanisms of this immune
the degradation of proteins that may limit their effectiveness resistance. By understanding mechanisms of immune
(158, 159). resistance, we can enable immunotherapy to provide more
ACT can be a potent new addition to the toolbox for cancer survival benefits for cancer patients.
immunotherapy. However, many TCR-T/CAR-T clinical trials Compared with single-drug therapy, combination strategy
have been hampered by off-target effects and safety concerns for immunotherapy has a greater clinical effect. Clinical trials
(160, 161). While timely intervention is effective in most adverse have shown that immunotherapeutic anticancer drugs, which
events, side-effect management of ACT must be held in the include ICBs, ACT, chemotherapy, targeted therapy, etc., are
whole process of ACT treatment. If tumor antigens are blocked important components of the combination. A few combination
by the self-secretion of tumor cells, they cannot be recognized by therapies have been approved by the FDA to improve clinical
the immune system. Rationally designed strategies to identify efficacy of cancer immunotherapy. With increasing research in
candidate neoantigens and evaluate their immunogenicity are identifying reliable biomarkers in guiding clinical immuno-
valuable for boosting the safety and efficacy of ACT. At present, oncology decisions, more convincing and effective
the successful ACT therapy is mainly used in the treatment of combination strategies are expected.
hematological tumors. In solid tumors, getting CAR-T cells to As the development of tumor immunology, bioinformatics,
infiltrate the tumor is a challenge, which can be compounded by and sequencing technologies, more and more mechanisms in
the immunosuppressive TME. ACT combined with small TME will continue to be revealed. This will further the

Liu et al. 10.3389/fimmu.2022.961805
development of cancer immunotherapy and pave the way for Minhang Hospital (RO-MY201712) (DZ), and Jinan Science
effective cancer treatments in the future. and Technology Bureau, Innovation team for the development
and evaluation of new drugs for oncology immunotherapy
(2020GXRC041 to DZ).
Author contributions
CL prepared the figures and tables and prepared the
manuscript; MY and MC contributed the idea and edited the Conflict of interest
manuscript; DZ participated in this study and contributed
project administration and funding acquisition; DZ The authors declare that the research was conducted in the
contributed the idea, oversaw the process and wrote the absence of any commercial or financial relationships that could
manuscript. All authors contributed to the article and be construed as a potential conflict of interest.
approved the submitted version.
Publisher’s note
Funding
All claims expressed in this article are solely those of the
The current study was supported by projects on the authors and do not necessarily represent those of their affiliated
S c i e n c e a n d T e c h n o l o g y C o m mi s si o n o f S h a n gh a i organizations, or those of the publisher, the editors and the
(18ZR1403900) (DZ), the National Natural Science reviewers. Any product that may be evaluated in this article, or
Foundation of China (81872895) (DZ), a project on joint claim that may be made by its manufacturer, is not guaranteed
translational research in the School of Pharmacy and or endorsed by the publisher.
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TYPE Review

PUBLISHED 11 October 2022

Clinical cancer immunotherapy:

Frontiers in Immunology 01 frontiersin.org

Frontiers in Immunology 02 frontiersin.org

TABLE 1 FDA-approved mAbs (Up to March 2022).

Target Name Company Year of launched Mechanism of Action

CD20 Rituximab Roche 1997 CDC, ADCC, ADCP

Frontiers in Immunology 03 frontiersin.org

Frontiers in Immunology 04 frontiersin.org

Frontiers in Immunology 05 frontiersin.org

Target Name Structure Company Highest Development Phases

PD-L1/VISTA CA-170 Aurigene, Curis Phase II (NCT01288911)

PD-L1 INCB-086550 Incyte Phase II (NCT04629339)

PD-L1 GS-4224 Gliead Phase 1b/2 (NCT04049617)

PD-1 MX-10181 undisclosed Maxinovel Phase I (NCT04122339)

Frontiers in Immunology 06 frontiersin.org

Target Name Structure Company Highest Development Phases

IDO1 BMS-986205 Bristol-Myers Squibb Phase III (NCT03661320)

IDO1 INCB-024360 Incyte Phase III (NCT02752074)

STING ADU-S100 Aduro, Novartis Phase II (NCT03937141)

STING MK-1454 Merck Phase II (NCT04220866)

A2AR AZD4635 AstraZeneca Phase II (NCT04089553)

A2AR NIR178 Novartis Phase II (NCT03207867)

Frontiers in Immunology 07 frontiersin.org

Target Name Structure Company Highest Development Phases

CXCR2 AZD5069 AstraZeneca Phase II (NCT03177187)

CXCR4 Mavorixafor X4 Pharmaceuticals Phase III (NCT03995108)

CCR2/5 BMS-813160 Bristol-Myers Squibb Phase II (NCT03184870)

TLR7 Imiquimod 3M Pharmaceuticals Marketed

TLR8 Motolimod Array Pharma, Celgene Phase I/II (NCT02431559)

ARG INCB001158 Calithera Biosciences, Incyte Phase I/II (NCT02903914)

Frontiers in Immunology 08 frontiersin.org

Frontiers in Immunology 09 frontiersin.org

Category Target Name Company Highest Development Phases

CAR-T CD19 Kymriah Novartis Marketed

Frontiers in Immunology 10 frontiersin.org

Tumor-inﬁltrating lymphocytes (TILs) are immune cells

Frontiers in Immunology 11 frontiersin.org

Virus Name Company Highest Development Phases

HSV-1 T-VEC AMGEN Marketed (FDA)

Frontiers in Immunology 12 frontiersin.org

TABLE 5 Research progress of therapeutic cancer vaccines (Up to April 2022).

Name Company Highest Development Phases

Provenge Dendreon Marketed (FDA)

Frontiers in Immunology 13 frontiersin.org

Frontiers in Immunology 14 frontiersin.org

Frontiers in Immunology 15 frontiersin.org

Radiotherapy promotes the release of TAAs, TSAs, or Other combination immunotherapies

Frontiers in Immunology 16 frontiersin.org

Frontiers in Immunology 17 frontiersin.org

Frontiers in Immunology 18 frontiersin.org

Frontiers in Immunology 19 frontiersin.org

Frontiers in Immunology 20 frontiersin.org

Frontiers in Immunology 21 frontiersin.org

Frontiers in Immunology 22 frontiersin.org

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