RESEARCH ARTICLE https://doi.org/10.1158/2767-9764.

CRC-24-0082 OPEN ACCESS

First-in-human Phase I Trial of TPST-1120, an Check for

updates

Inhibitor of PPARα, as Monotherapy or in

Combination with Nivolumab, in Patients
with Advanced Solid Tumors

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Mark Yarchoan1 , John D. Powderly2 , Bruno R. Bastos3 , Thomas B. Karasic4 ,
Oxana V. Crysler5 , Pamela N. Munster6 , Meredith A. McKean7 , Leisha A. Emens8 ,
Yvonne M. Saenger9 , Yasser Ged1 , Robert Stagg10 , Steven Smith10 , Chan C. Whiting10 ,
Anne Moon10 , Peppi Prasit10 , Yonchu Jenkins10 , Nathan Standifer10 , Thomas W. Dubensky10 ,
Sam H. Whiting10 , and Susanna V. Ulahannan11

ABSTRACT
Purpose: TPST-1120 is a first-in-class oral inhibitor of peroxisome ported. In the monotherapy group, 53% (10/19) of evaluable patients had
proliferator-activated receptor α (PPARα), a fatty acid ligand-activated a best objective response of stable disease. In the combination group, 3 pa-
transcription factor that regulates genes involved in fatty acid oxidation, tients had partial responses, for an objective response rate of 20% (3/15)
angiogenesis, and inflammation, and is a novel target for cancer therapy. across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Re-
TPST-1120 displayed antitumor activity in xenograft models and syner- sponses occurred in 2 patients with RCC, both of whom had previously
gistic tumor reduction in syngeneic tumor models when combined with progressed on anti-PD-1 therapy, and 1 patient with late-line CCA.
anti-PD-1 agents. Conclusions: TPST-1120 was well tolerated as monotherapy and in combi-
Experimental Design: This phase I, open-label, dose-escalation study nation with nivolumab and the combination showed preliminary evidence
(NCT03829436) evaluated TPST-1120 as monotherapy in patients with ad- of clinical activity in PD-1 inhibitor refractory and immune compromised
vanced solid tumors and in combination with nivolumab in patients with cancers.
renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellu- Significance: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose
lar carcinoma. Objectives included evaluation of safety, pharmacokinetics, roles in metabolic and immune regulation are implicated in tumor prolifer-
pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). ation/survival and inhibition of anticancer immunity. This first-in-human
Results: A total of 39 patients enrolled with 38 treated (20 monother- study of TPST-1120 alone and in combination with nivolumab sup-
apy, 18 combination; median 3 prior lines of therapy). The most common ports proof-of-concept of PPARα inhibition as a target of therapeutic
treatment-related adverse events (TRAE) were grade 1–2 nausea, fatigue, intervention in solid tumors.
and diarrhea. No grade 4–5 TRAEs or dose-limiting toxicities were re-

Introduction cancer is an increase in aerobic glycolysis (the Warburg effect), cancer cells
can utilize other metabolic pathways such as increased fatty acid oxidation
Metabolic reprogramming and evasion of immune destruction are hallmarks (FAO) to support tumorigenesis. FAO also promotes stemness, drug resistance,
of cancer (1). While the most widely recognized metabolic adaptation in and metastasis (2–4), and modulates immune cell function within the tumor

University of Oklahoma/Sarah Cannon Research Institute, Oklahoma City,

1
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Oklahoma.
Maryland. 2 Carolina BioOncology Institute, Huntersville, North Carolina. 3 Baptist Corresponding Author: Mark Yarchoan, Johns Hopkins Sidney Kimmel
Health Miami Cancer Institute, Miami, Florida. 4 Abramson Cancer Center at the Comprehensive Cancer Center, 1650 Orleans St., CRB1, 4M08, Baltimore, MD 21231.
University of Pennsylvania, Philadelphia, Pennsylvania. 5 University of Michigan E-mail: [email protected]
Rogel Cancer Center, Ann Arbor, Michigan. 6 UCSF Health – UCSF Medical Center, doi: 10.1158/2767-9764.CRC-24-0082
San Francisco, California. 7 Sarah Cannon Research Institute, Nashville, Tennessee.
8
UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. 9 Herbert Irving This open access article is distributed under the Creative Commons Attribution 4.0
Comprehensive Cancer Center, Columbia University, New York, New York. International (CC BY 4.0) license.
10
Tempest Therapeutics, Brisbane, California. 11 Stephenson Cancer Center of the © 2024 The Authors; Published by the American Association for Cancer Research

AACRJournals.org Cancer Res Commun; 4(4) April 2024 1100

 PPARα Inhibition in Patients with Advanced Solid Cancers

microenvironment, which enables tumors to evade antitumor immune re- Patient Selection
sponses (5–7). Enhanced FAO is described in multiple cancers and has been
Key inclusion criteria included diagnosis of advanced/metastatic solid tumor
reported to correlate with poor patient outcomes (8).
previously treated with standard systemic therapy for the disease; Eastern
Peroxisome proliferator-activated receptor α (PPARα) is a fatty acid ligand- Cooperative Oncology Group (ECOG) performance status of 0–1 with es-
activated transcription factor that controls the expression of over 100 genes timated life expectancy of at least 12 weeks; adequate organ function; and
involved in FAO, angiogenesis, and inflammation (9–11). PPARα is crit- measurable disease according to the RECIST version 1.1. Tumor types eligi-
ical for maintaining physiologic metabolic homeostasis under conditions ble for monotherapy dose escalation [cholangiocarcinoma (CCA), colorectal
when fatty acids are the predominant source of energy, such as during cancer, metastatic castration-resistant prostate cancer, gastroesophageal can-
fasting or diet-induced lipid overload. In addition to upregulating genes cer, hepatocellular carcinoma (HCC), non–small cell lung cancer, pancreatic
involved in FAO, activated PPARα dampens Th1-promoting inflammatory cancer, renal cell carcinoma (RCC), sarcoma, head and neck squamous cell
responses to metabolic disturbances by directly enhancing transcription of carcinoma, triple-negative breast cancer, and urothelial bladder cancer] were
anti-inflammatory proteins, such as IκBα, and by antagonizing the activity selected based upon elevated expression of PPARA and associated genes
of proinflammatory transcription factors, such as NFκB and AP-1, through in The Cancer Genome Atlas in these indications. In the nivolumab com-

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transrepression, a mechanism involving direct protein–protein interactions bination portion of the study, eligible tumor types were limited to those
(12, 13). displaying the highest expression of PPARA and associated genes: clear
cell RCC, CCA, and HCC (16). Key exclusion criteria included history
Because of its critical roles in metabolic regulation and immune function,
of intolerable or unresolved immune-related adverse event (AE) resulting
PPARα has emerged as a target of interest for cancer therapy. The dual effect
from prior immune checkpoint inhibitor (ICI) therapy; ongoing use of im-
of PPARα both promoting tumor cell growth and inhibiting anticancer immu-
munosuppressive medications or active autoimmune disease; untreated/active
nity is supported by preclinical experiments in which Ppara deficiency in either
central nervous system metastases; or use of fibrates within 28 days of
implanted tumor cells or recipient host reduced tumor growth in vivo, while
enrollment.
Ppara deficiency in both implanted tumor cells and recipient host resulted in
significantly greater tumor inhibition than in either compartment alone (14).
The critical antitumor role of PPARα inhibition specifically in immune cells Treatment Plan
was further demonstrated in chimeric animals where bone marrow from Ppara
Monotherapy TPST-1120 was administered orally in 21-day cycles until disease
knockout (KO) mouse transplanted into a Ppara wild-type animal, but not the
progression or unacceptable toxicity with a starting dose of 100 mg twice daily
reverse, profoundly inhibited tumor growth (14).
(200 mg/day). In a standard 3+3 design, patients were sequentially enrolled at
TPST-1120 is a first-in-class, oral, small molecule, competitive antagonist of progressively higher dose levels of TPST-1120, evaluating 100, 200, 300, 400, and
PPARα, with nanomolar potency (IC50 0.04 μmol/L) for human PPARα and 600 mg twice daily.
high specificity (>250-fold) for PPARα over the other PPAR isoforms (PPAR
Dose escalation of TPST-1120 in combination with nivolumab was initiated
β/δ and γ; ref. 15). In xenograft and syngeneic tumor models, TPST-1120 inhib-
after the 300 mg twice daily (600 mg/day) monotherapy cohort successfully
ited tumor growth in vivo as monotherapy, and the combination of TPST-1120
cleared the dose-limiting toxicity (DLT) evaluation period. TPST-1120 was eval-
plus anti-PD-1 therapy resulted in synergistic tumor reduction and durable an-
uated in 28-day cycles at progressively higher dose levels of 200, 300, 400,
titumor immunity in multiple syngeneic mouse models (16). Adoptive transfer
and 600 mg orally twice daily in combination with standard dose nivolumab
of splenocytes from syngeneic mice bearing MC38 colon tumors treated and
(480 mg intravenous infusion every 4 weeks). Treatment continued until
cured with TPST-1120 plus anti-PD-1 conferred resistance to tumor challenge
disease progression or unacceptable toxicity.
in naïve mice, similar to the results observed in Ppara KO studies (16). This
first-in-human study was conducted to evaluate TPST-1120 as monotherapy In all dose cohorts, TPST-1120 was taken with food and with water. Patients
and in combination with the PD-1 inhibitor nivolumab in patients with select were required to fast for a minimum of 8 hours prior to protocol-specified lab-
advanced solid tumors. oratory assessments on cycle 1 day 1, cycle 1 day 8, cycle 2 day 1, and cycle 3
day 1.

Materials and Methods

Study Design Efficacy and Safety Assessments
This was a first-in-human, phase I, open-label, 3+3 design, dose-escalation Safety was assessed on the basis of incidence of AEs, laboratory results, and
study (ClinicalTrials.gov identifier: NCT03829436). The primary study ob- physical examinations on day 1 and day 8 of the first cycle, then on day 1 of each
jectives were to investigate the safety and tolerability, and to determine subsequent cycle. AEs were recorded by Common Toxicity Criteria for Adverse
the MTD or optimal biological dose (OBD), of TPST-1120 as monother- Events v5.0 from the first dose of study therapy through 28 days after the last
apy and in combination with nivolumab. Key additional objectives included dose for monotherapy and 90 days after the last treatment dose for combination
evaluation of pharmacokinetics, pharmacodynamics, and preliminary assess- therapy.
ment of anticancer activity. Exploratory objectives included investigation of
Disease assessments using CT scans or MRI were performed at baseline and
immunomodulatory effects of treatment in peripheral blood.
on day 1 of cycle 3, day 1 of cycle 5, and every 9 weeks thereafter for monother-
The trial was designed by employees of the study Sponsor, Tempest apy, and day 1 of every odd cycle thereafter for combination therapy. Antitumor
Therapeutics, in collaboration with the study investigators. response was assessed using RECIST v1.1.

AACRJournals.org Cancer Res Commun; 4(4) April 2024 1101

 Yarchoan et al.

Pharmacokinetics and Pharmacodynamics Overall response rate (ORR) was defined as the proportion of patients with
complete response or partial response (PR). Disease control rate (DCR) was de-
Blood for pharmacokinetic and research assessments was collected at screening,
fined as ORR + SD of at least one scan. The efficacy population (EP) comprised
cycle 1 days 1, 2, and 8, cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 (combination
all safety-evaluable patients who had at least one postbaseline tumor assess-
only), and cycle 5 day 1 (monotherapy only). Tumor biopsies were not required.
ment, as well as patients who discontinued from study treatment due to PD
Plasma TPST-1120 concentrations were quantified using a validated tandem without undergoing a follow-up radiographic assessment.
mass spectrometry assay. Noncompartmental analysis was performed on ob-
served data following the first dose and at steady state on day 8. To assess Study Approval
pharmacodynamic gene expression changes, RNA was extracted from whole
This study was reviewed and approved by the individual site Institutional Re-
blood samples collected in PAXgene Blood RNA tubes on cycle 1 days 1 and 8
view Boards and/or ethics committees where the study was opened and by
and cycle 3 day 1 and assayed on the nCounter instrument (NanoString, Inc.)
the FDA. The study was conducted in accordance with the provisions of the
using the nCounter PanCancer Immune Profiling panel supplemented with an
Declaration of Helsinki and the International Conference on Harmonization
additional 30 PPARα-associated genes (Supplementary Table S1) according to
Guidelines for Good Clinical Practice. All patients provided written informed

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manufacturer’s protocols. Associations between gene expression changes and
consent.
TPST-1120 exposure levels were assessed by linear regression analysis between
AUC0–24 and baseline-normalized values on day 8, adjusting for the FDR using
Data Availability
the method of Benjamini and Hochberg (ref. 17; FDR P < 0.05) and demon-
strating an effect size greater than 0.5. Similar exposure-related changes in The data generated in this study are available upon request from the
expression had to be observed on cycle 3 day 1 for a gene to be denoted as a phar- corresponding author.
macodynamic biomarker. Differences in gene expression change magnitudes
between exposure tertiles were assessed using Wilcoxon pairwise method (α =
0.05). To identify associations of gene changes with clinical response, patients Results
were stratified on the basis of best overall response (BOR), and linear discrim- Patient Characteristics
inant analysis (LDA) was performed to identify gene expression changes on
Between May 13, 2019 and September 07, 2022, a total of 39 patients enrolled at
day 8 associated with each response category. Change magnitudes of identified
11 centers in the United States: 21 in the monotherapy cohort and 18 in the com-
genes were compared between partial responders and stable disease (SD) or
bination therapy cohort. One of the 21 patients enrolled in the monotherapy
progressive disease (PD) patients using Mann–Whitney U tests (α = 0.05).
cohort withdrew consent prior to treatment initiation and was not included in
Lipidomics analysis was performed by the UCLA Lipidomics Lab using a the analysis. The baseline characteristics of the study population are presented
LC/MS technique, as described previously (18). Data were analyzed using the in Table 1. The mean age was 61.7 years in the monotherapy cohort (range, 41–
method of Su and colleagues (19). 78 years) and 63.4 years in the combination therapy cohort (range, 43–84 years).
In the monotherapy cohort, the primary malignancies were pancreatic cancer
DLT Definition and OBD Determination [8 (40.0%) patients], CCA [5 (25.0%) patients], and colorectal cancer [4 (20.0%)
Dose escalation followed a standard 3+3 design with a minimum of 3 pa- patients]. In the combination therapy cohort, 9 patients (50.0%) had a primary
tients assigned per dose level. If 0 of 3 or 1 of 6 patients experienced a DLT, diagnosis of CCA, while the rest had diagnoses of RCC [5 (27.8%) patients] or
dose-escalation continued to the next higher dose level cohort until the MTD HCC [4 (22.2%) patients]. The median number of prior systemic therapies was
was identified or evaluation of the top protocol-defined dose level was com- 3 (range, 2–9) for monotherapy and 3 (range, 1–6) for combination patients. In
pleted. Six patients were to be enrolled in the highest dose level cohort that did the combination cohort, all patients with HCC or RCC had received at least one
not exceed the MTD. The MTD was exceeded if >1 of 3 or ≥2 of 6 patients prior anti-PD-(L)1 therapy as part of standard of care and had discontinued the
experienced a DLT. most recent anti-PD-(L)1 therapy for disease progression.

DLTs were evaluated during the first treatment cycle (21 days for monother-
Pharmacokinetics
apy and 28 days for TPST-1120 plus nivolumab). Patients were evaluable for
DLTs if they received at least 85% of planned TPST-1120 doses (and all planned Data from 31 patients were available for pharmacokinetic analysis on day 8.
nivolumab doses for combination patients) in the first treatment cycle un- TPST-1120 steady-state exposure levels increased in a linear, dose-dependent
less this exposure threshold was not met due to a DLT. Patients who did manner and were not affected by nivolumab (Supplementary Fig. S1). Key phar-
not meet the DLT evaluability criteria were replaced. AEs occurring dur- macokinetic parameters of patients receiving TPST-1120 at 600 mg following
ing the first treatment cycle and assessed as related to study treatment were single dose and at steady state are listed in Supplementary Table S2.
considered DLTs following criteria established in the study protocol. OBD
determination was based on emerging pharmacokinetics, any pharmacoki- Safety
netic/pharmacodynamic relationships which could be established, and overall No DLTs occurred during dose escalation. Two monotherapy patients (1 at
safety and tolerability. 200 mg twice daily and 1 at 400 mg twice daily) were not evaluable for DLTs
due to missing more than 15% of the required TPST-1120 doses during the eval-
Statistical Methods uation period due to AEs unrelated to treatment and were replaced. An MTD
Analysis was performed using descriptive statistics. All patients who received was not established for TPST-1120 as monotherapy or in combination with
at least one dose of TPST-1120 were included in the safety analysis. nivolumab.

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 PPARα Inhibition in Patients with Advanced Solid Cancers

TABLE 1 Demographics and patient characteristics of the monotherapy and combination cohorts

TPST-1120 TPST-1120 +
Monotherapy Nivolumab
Baseline characteristics (n = 20) (n = 18)

Age, mean, years (range) 61.7 (41–78) 63.4 (43–84)

Female, n (%) 10 (50) 9 (50)
TPST-1120 dose, n (%) 100 mg BID 3 (15) —
200 mg BID 4 (20) 3 (17)
300 mg BID 3 (15) 3 (17)
400 mg BID 4 (20) 3 (17)
600 mg BID 6 (30) 9 (50)
Primary cancer type, n (%) Castration-resistant prostate cancer 1 (5) —

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Cholangiocarcinoma 5 (25) 9 (50)
Colorectal cancer 4 (20) —
Hepatocellular carcinoma 1 (5) 4 (22)
Non–small cell lung cancer 1 (5) —
Pancreatic cancer 8 (40) —
Renal cell carcinoma — 5 (28)
Prior systemic regimens Median (range) 3 (2–9) 3 (1–6)
Prior α-PD-1/α-PD-L1, n (%) 6 (30) 10 (56)
ECOG PS, n (%) 0 5 (25) 8 (44)
1 15 (75) 10 (56)

Abbreviations: BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status.

In the monotherapy cohort, 10 patients (50%) experienced an AE that was was assessed as treatment-related. There were no grade 4 or grade 5 TRAEs,
deemed as related to TPST-1120 (Table 2). The most frequently reported and no patient discontinued study treatment due to a TRAE.
treatment-related AEs (TRAE) were nausea [4 (20%) patients], fatigue [3 (15%)
In the combination therapy cohort, 14 patients (77.8%) experienced TRAEs re-
patients], and diarrhea [2 (10%) patients], all grade 1–2. One patient experi-
lated to either TPST-1120 or nivolumab (Table 2). The most frequent TRAEs
enced grade 3 hypertension at the 600 mg twice daily dose of TPST-1120 that
were fatigue [6 (33.3%) patients], diarrhea [4 (22%) patients], and nausea [3
(17%) patients], all grade 1–2. Three patients experienced grade 3 TRAEs:
1 each of arthralgia (TPST-1120 400 mg twice daily), hepatic enzymes in-
TABLE 2 Treatment-related treatment-emergent AEs by preferred
creased (TPST-1120 600 mg twice daily), and muscle spasms (TPST-1120 600 mg
term in ≥1 patient, any grade and grade 3
twice daily). Two of these TRAEs (grade 3 arthralgia and grade 3 hepatic en-
AE, n (%) Grades 1–3a Grade 3 zymes increased) were considered immune-related and treated with systemic
steroids. There were no grade 4 or grade 5 TRAEs. The patient with grade 3
TPST-1120 Monotherapy (n = 20) hepatic enzymes increased was the sole patient treated with combination ther-
Patients with ≥1 TRAE 10 (50.0) 1 (5.0) apy (TPST-1120 600 mg orally twice daily) to discontinue treatment due to
Nausea 4 (20.0) — a TRAE.
Fatigue 3 (15.0) —
Diarrhea 2 (10.0) —
Efficacy
Hypertension 1 (5.0) 1 (5.0)
Clinical efficacy for TPST-1120 monotherapy and in combination with
TPST-1120 + Nivolumab (n = 18)
nivolumab is summarized in Fig. 1. Four treated patients were not included
Patients with ≥1 TRAEb 14 (77.8) 3 (16.7)
in the EP due to discontinuation of treatment for either symptomatic deteri-
Fatigue 6 (33.3) —
oration without objective evidence of PD (1 monotherapy, 1 combination) or
Diarrhea 4 (22.2) —
due to unrelated AE (2 combination patients) prior to obtaining a postbaseline
Nausea 3 (16.7) —
tumor assessment. The monotherapy efficacy evaluable population included
Abdominal pain 2 (11.1) —
3 patients who did not have a postbaseline RECIST assessment but discon-
Arthralgia 1 (5.6) 1 (5.6)
tinued treatment for investigator-assessed disease progression not confirmed
Hepatic enzyme increased 1 (5.6) 1 (5.6)
by RECIST. Among the 19 efficacy evaluable patients in the monotherapy co-
Muscle spasms 1 (5.6) 1 (5.6)
hort, the BOR was SD for 10 (53.0%) patients and PD for 6 (32.0%) patients,
a No grade 4 or 5 TRAEs. for a DCR of 53%. Tumor shrinkage of target lesions was observed in 4 patients
b Related to either TPST-1120 or nivolumab. (21%) with no target lesion growth as the best relative change from baseline in

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FIGURE 1 Clinical efficacy of TPST-1120 monotherapy (A, B) and in combination with nivolumab (C, D). In swimmer plots shown in A and C, study
treatment discontinuations for other than disease progression are shown as *Adverse event, ˆSymptomatic deterioration, # Investigator decision, or
§ Consent withdrawn. For monotherapy, scans were every 6 weeks until week 12, followed by an increase to 9-week intervals between scans. For

combination therapy, scans occurred every 8 weeks. The RCC responder in the 600 mg BID + nivolumab dose group had an unscheduled scan at day
24 during hospitalization for treatment-unrelated AEs. This patient discontinued treatment one day prior to the scan but was unable to restart and had
disease progression during the posttreatment follow-up period. BID, twice daily; CCA, cholangiocarcinoma; CRC, colorectal carcinoma; HCC,
hepatocellular carcinoma; mCRPC, metastatic castration-resistant prostate cancer; NSCLC, non–small cell lung cancer; Panc, pancreatic cancer; PD,
progressive disease; PR, partial response; RCC, renal cell carcinoma; SD, stable disease.

3 additional patients. Of the 10 patients who had SD, 5 (50%) were on treatment −31% but also a new lesion in a mixed response (Fig. 1D). One additional PR
>20 weeks. Among 5 patients with CCA, 3 had at least two assessments of SD, was achieved in a patient with heavily pretreated CCA that was PD-L1 nega-
including 1 patient who was on treatment for almost 10 months before discon- tive, mismatch repair proficient, with a tumor mutational burden of 10 mut/Mb;
tinuing due to symptomatic deterioration while still meeting RECIST for SD he had received six prior lines of systemic therapy before study enrollment
(Fig. 1A; Supplementary Fig. S2). (Fig. 2B).

Of the 15 response-evaluable patients in the combination therapy cohort, 3 Notably, both patients with RCC who responded to the TPST-1120 combina-
patients (20.0%) achieved a PR (1 confirmed), while a best response of SD oc- tion regimen (and the patient with RCC with a −31% mixed response) were
curred in 3 patients (20%), and 9 patients (60%) had PD. All responders were previously treated with at least one anti-PD-1 containing regimen with a best
treated at the two highest doses of TPST-1120 (≥400 mg twice daily) for an ORR response of SD and discontinued the most recent anti-PD-1 therapy for dis-
of 30% (3/10) at the 400 and 600 mg doses. In addition, of 4 evaluable patients ease progression. The RCC responder who achieved a −54% RECIST PR at
with RCC, 2 achieved a PR for an ORR of 50% in this indication (Fig. 2A for the first tumor assessment (8 weeks of treatment) had previously received
one of the responders) and a third demonstrated a target lesion regression of first-line ipilimumab + nivolumab followed by cabozantinib and everolimus,

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 PPARα Inhibition in Patients with Advanced Solid Cancers

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FIGURE 2 A, PR in a 54-year-old female with RCC who had disease progression on prior anti-PD-1 therapy. Prior treatment included ipilimumab +
nivolumab (first line), cabozantinib (second line), and everolimus (third line) with no better than SD on any regimen. She achieved a PR (−54%) after
8 weeks of treatment with TPST-1120 + nivolumab that deepened to −62% and was durable for more than 1 year. Changes in pulmonary lesions are
shown in CT chest scans taken during screening and on-treatment. SD, stable disease. B, PR in an 84-year-old male with heavily pretreated
extrahepatic cholangiocarcinoma. He had an initial increase in tumor burden followed by serial shrinking tumor scans before achieving a nadir of −34%
and an overall response of PR at scan 4. SLD: sum of longest diameters.

discontinuing each regimen for PD after a best response of SD. The RCC re- (FDR P < 0.05, effect size > 0.5, Fig. 3A). Similar associations between expres-
sponder who achieved a −30% RECIST PR had previously received first-line sion levels of these genes and TPST-1120 exposure were also observed on cycle 3
pembrolizumab + axitinib followed by cabozantinib and discontinued both day 1 (Supplementary Fig. S3). Modulated genes included FCGRIIA (CD32; ref.
regimens for disease progression after a best response of SD. 20), ITGAX (CD11c; ref. 21), TAP (22, 23), and TNFRSFA (CD120a; ref. 24), all
of which are gene targets of transcription factors inhibited by PPARα through
Biomarker Exploration transrepression (Table 3). Analysis of gene expression changes by exposure ter-
Analysis of differential expression levels of 780 genes in whole blood specimens tile demonstrated that median expression levels of three of the four target genes
revealed that four were increased as a function of TPST-1120 AUC0–24 on day 8 at the middle exposure tertile, 11,818–20,749 nghour/mL, were statistically

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FIGURE 3 Genes differentially expressed on treatment day 8 versus treatment baseline, as a function of TPST-1120 exposure. A, Linear associations
of day 8 log2 fold change in expression levels of indicated genes and TPST-1120 AUC0–24 . All genes exhibited FDR P < 0.05 and effect size > 0.5. Data
are shown for both TPST-1120 monotherapy (part 1) and TPST-1120 + nivolumab combination therapy (part 2). An AUC0–24 value of 66,180 nghour/mL
was excluded as an outlier. B, Comparison of differential gene expression on day 8 as a function of AUC0–24 tertile. Median elevation magnitudes in
highest tertile were statistically increased above baseline values (*, P < 0.05 by Wilcoxon pair-wise comparison).

elevated above that observed in the lowest tertile (P < 0.05 by Wilcoxon pair- Lipid analysis revealed on-treatment elevation in circulating free fatty acids
wise comparison, Fig. 3B). This corresponds to 60% of patients with TPST-1120 (FFA) from baseline to day 57 and day 85 in patients demonstrating PRs that
steady-state exposures of at least 11,819 nghour/mL who demonstrated target were not detected in patients with a best response of PD/SD (Supplementary
gene elevations above baseline levels and identifies a minimum exposure for Fig. S5).
induction of pharmacodynamic activity.

LDA of day 8 gene expression levels among BOR categories revealed clear dis- OBD Selection
tinctions in expression patterns between PD or SD patients and PR patients The 600 mg twice daily dose of TPST-1120 was determined as the OBD for both
(Supplementary Fig. S4A). PR patients were observed to express statisti- monotherapy and combination therapy regimens. Analysis of pharmacokinet-
cally decreased levels of CFB and PVR (CD155) and increased levels of ics across doses and for both monotherapy and combination showed a linear
APOE, MAGEA, RORC, and SYT (P < 0.05 by Mann–Whitney U test; relationship between TPST-1120 dose and plasma exposure, with no saturation
Supplementary Table S3; Supplementary Fig. S4B). at 600 mg twice daily, the highest dose level tested. Pharmacodynamic analysis

TABLE 3 Summary of genes associated with TPST-1120 exposure levels

FDR Transcription factor

P-value, associated with PPARα
Gene Name Function in immune cells effect size transrepression

FCGR2A Fc-γ RIIa, CD32 Enhances antibody-dependent cytotoxicity of tumor 0.047, 0.732 STAT1 (20)
cells, increased phagocytosis and cytokine release
by myeloid cells (25)
ITGAX Integrin α-X, CD11c Marker of conventional dendritic cells that 0.049, 0.566 Fos, Jun, C/EBP (21)
cross-present tumor antigens, enhances
phagocytosis of tumor cells by macrophages (26)
TAP1 Transporter associated with Increases endogenous antigen processing and 0.049, 0.550 STAT1 (22), NFκB (23)
antigen processing-1 presentation by MHC-I molecules
TNFRSF1A TNFα R1, CD120a Enhances responsiveness to TNFα, activates 0.047, 0.648 STAT3 (24)
NFκB-responsive genes (27)

Abbreviation: FDR, false discovery rate.

1106 Cancer Res Commun; 4(4) April 2024 https://doi.org/10.1158/2767-9764.CRC-24-0082 | CANCER RESEARCH COMMUNICATIONS
 PPARα Inhibition in Patients with Advanced Solid Cancers

of the association between TPST-1120 steady-state exposures and gene expres- factors that are subject to PPARα transrepressive activities, including NFκB
sion changes in peripheral blood demonstrated exposure-dependent increases and STAT1. This transcriptional dose–response allows for establishment of a
in expression of a subset of genes known to be regulated by transcription factors minimum exposure threshold for pharmacodynamic activity corresponding
transrepressed by PPARα, and the identified minimum exposure for induction to a TPST-1120 dose of at least 400 mg twice daily. Consistent with the ex-
of pharmacodynamic activity was achieved in all patients receiving TPST-1120 posure threshold, all patients who achieved a PR were dosed with TPST-1120
at 400 or 600 mg twice daily (Supplementary Fig. S1). Review of safety data at ≥400 mg twice daily. Further exploratory analyses of associations between
showed no evidence of dose-dependent toxicity through the highest dose tested BOR and changes in both gene expression and lipids in study patients showed
of 600 mg twice daily, either for single agent TPST-1120 or when administered increases in circulating FFA levels, indicating a reduction in lipid catabolism,
with nivolumab. Finally, although limited by small numbers, RECIST responses and increases in RORC, encoding RORγt, the master transcriptional regulator
in the combination cohort all occurred at the two highest TPST-1120 dose levels of Th17 cells, consistent with literature reports that Th17 cells are increased in
tested, consistent with dose-responsive antitumor activity. PPARα-deficient animals (35, 36).

The increased expression of genes downstream of proinflammatory tran-

Discussion scription factor targets of PPARα transrepression suggests that immune cell

Downloaded from http://aacrjournals.org/cancerrescommun/article-pdf/4/4/1100/3442866/crc-24-0082.pdf by guest on 26 June 2024

function is enhanced with TPST-1120 treatment. These results are consis-
TPST-1120 is a novel investigational agent designed to therapeutically target
tent with literature indicating PPARα deficiency increases inflammation, one
cancer cells and enhance anticancer immunity by inhibiting the fatty acid
such example being the promotion of M1 macrophage polarization by Ppara
ligand-activated transcription factor PPARα. In this phase I first-in-human
KO in myeloid cells—shown as increased IL1 and TNFα mRNA and de-
study, which is the first to report clinical data on PPARα modulation in solid
creased arginase mRNA expression upon lipopolysaccharide stimulation of
tumors, we tested the hypothesis that inhibiting PPARα with TPST-1120 would
bone marrow–derived macrophages (37). Lack of PPARα, as well as treat-
be tolerable in patients with advanced cancer and would have anticancer ac-
ment with the PPARα antagonist IS001, resulted in increased IFNγ production
tivity. TPST-1120 was well tolerated both as monotherapy and in combination
by CD4+ and CD8+ T lymphocytes and natural killer T cells (38). Corre-
with the PD-1 inhibitor, nivolumab, including no DLTs during dose escalation
spondingly, augmented or sustained responses to inflammatory stimuli across
and predominantly grade 1–2 and manageable TRAEs. In the 18 patients who
multiple models of inflammation were observed when Ppara was deleted and
received TPST-1120 in combination with nivolumab, there was no evidence of
support a role for PPARα in immune regulation (39–41).
synergistic or unexpected toxicity, and the AEs were consistent with the profiles
of the two drugs. In characterizing the antitumor activity of TPST-1120, it is of interest whether
these dual PPARα functions—transrepression associated with immunomod-
TPST-1120 also showed evidence of clinical activity. In the monotherapy group,
ulatory activity and PPAR response element (PPRE)-mediated transcription
disease control including target lesion shrinkage was demonstrated in a sub-
controlling lipid metabolism—are linked, as increased utilization of FAO is a
set of patients with highly refractory pancreatic, CCA, and late-line colorectal
well-studied metabolic characteristic of suppressive immune cells. Experiments
cancers. The combination of TPST-1120 and nivolumab demonstrated an ORR
conducted using a mutant PPARα protein unable to activate transcription of
of 20% across all doses and 30% at the two highest doses of TPST-1120. Re-
PPRE-dependent genes and consequently devoid of its lipid-regulating activ-
sponses were seen in patients with RCC previously refractory to ICI therapy
ity, showed that mutant PPARα retained the ability to attenuate inflammation
and in a patient with late-line, PD-L1–negative and microsatellite stable CCA—
in a mouse model of liver fibrosis, demonstrating that these two functions can
a tumor type poorly responsive to ICI monotherapy (e.g., pembrolizumab ORR
be uncoupled and are distinct (42). Future preclinical work will focus on dis-
of 2.9% in patients with PD-L1 combined positive score ≤1 treated in the
secting the contribution of each function to the antitumor activity displayed by
KEYNOTE-158 trial; refs. 28–31). It is notable that among 4 evaluable patients
TPST-1120.
with RCC, 2 (50%) achieved a PR with the TPST-1120 + nivolumab combina-
tion, including a deep and very durable response in a patient who had already Limitations of this study include small numbers of patients treated at different
progressed on nivolumab + ipilimumab after achieving SD as best response. In TPST-1120 dose levels. In addition, imbalanced enrollment of pancreaticobil-
a recent prospective randomized phase III study, the addition of atezolizumab iary cancers in the monotherapy cohort reduced the assessment of the PPARα
to cabozantinib provided no additional benefit compared with cabozantinib inhibition mechanism in other solid tumor types. Evaluation of TPST-1120
alone in second-line treatment of patients with RCC who had received ICI treat- pharmacodynamic activity was restricted to the challenging and complex set-
ment in first line (32). In retrospective reports, the ORR of patients with RCC ting of peripheral blood cells and circulating lipids by the lack of fresh tumor
treated with nivolumab monotherapy after previous ICI therapy was 16% (33) biopsies.
and 23% (34). Acknowledging the limitation of small patient numbers, these
Further clinical development of TPST-1120 in RCC and CCA is planned based
response data in immunotherapy-refractory patients are consistent with the
upon these study results. A separate study is ongoing in HCC, a tumor type not
preclinical results showing that TPST-1120 modulates the immune phenotype
adequately represented in this phase I study, but of particular interest due to the
away from suppressor populations and combines synergistically with anti-PD-
high expression of PPARα. A global randomized phase Ib/II study is evaluating
1 therapy (16), and consistent with the literature that genetic KO of PPARα
the combination of atezolizumab plus bevacizumab, with or without TPST-1120,
increases inflammation and decreases tumor growth in mouse models (14).
in patients with first-line advanced HCC (NCT04524871). Initial efficacy results
Further supporting the immune mechanism, an exploratory analysis of gene from this randomized study are encouraging and have been publicly reported
expression changes in whole blood of patients treated in this study demon- (43). The identification of novel biomarkers that correlate with sensitivity to
strated TPST-1120 exposure-dependent increases in the expression of genes TPST-1120 may further improve patient selection for future trials and inform
transcriptionally regulated by Th1-promoting proinflammatory transcription the development of novel therapeutic combinations.

AACRJournals.org Cancer Res Commun; 4(4) April 2024 1107

 Yarchoan et al.

Authors’ Disclosures Next Cure, Silverback, and Takeda outside the submitted work; and consult-
ing for AstraZeneca, Bioline Rx, DNAMx, Genentech, Roche, GPCR, Gilead,
M. Yarchoan reports grants and personal fees from Genentech; grants from Immune Onc, Immunitas, Immutep, Lilly, Macrogenics Mersana, Shionogi
Bristol Myers Squibb and Incyte; personal fees from Exelixis, Eisai, As- member SAB Bioline RX member CAB Immutep potential for equity with
traZeneca, Replimune, Hepion, Lantheus; and other from Adventris outside Ankyra Therapeutics potential for future royalties from Molecuvax. R. Stagg
the submitted work. J.D. Powderly reports personal fees and other from reports personal fees and other from Tempest outside the submitted work;
Tempest Therapeutics during the conduct of the study; other from Carolina and Clinical consultant for Tempest Therapeutics. S. Smith reports personal
BioOncology Institute, PLLC, BioCytics Inc., Genentech Roche, AstraZeneca fees from Tempest Therapeutics during the conduct of the study. C.C. Whiting
Medimmune, AbbVie, Aavocyte, AavoBioCytics, Phanes Therapeutics, BMS, reports other from Tempest Therapeutics outside the submitted work; in addi-
EMD Serono, Macrogenics, Top Alliance BioSciences, Alkermes, Calico, tion, C.C. Whiting has a patent to us2023/078674 pending. A. Moon reports
Atreca, Precision for Medicine, Stem Cell, Sequenom, Replimuune, Engi- personal fees, non-financial support, and other from Tempest Therapeutics
neered BioPharmaceuticals, Therapeutic Brainpower, Merck, PIOMA, Xilis, during the conduct of the study. P. Prasit reports other from Tempest Therapeu-
Repertoire Immune Medicines, NextCure, Xilio Therapeutics, Nuvation Bio, tics outside the submitted work. N. Standifer reports other from AstraZeneca,

Downloaded from http://aacrjournals.org/cancerrescommun/article-pdf/4/4/1100/3442866/crc-24-0082.pdf by guest on 26 June 2024

Cullinan Oncology, Immune-Onc Therapeutics, Trethera, Fate Therapeutics, Amgen, Tempest Therapeutics, and personal fees from Vincerx outside the
Conjupro BioTherapeutics, Ascendis Pharma, PEEL Therapeutics, CUE Bio- submitted work; in addition, N. Standifer has a patent to Triazolone com-
Pharma, Pieris Pharmaceuticals, RiboScience, Moderna TX, SK Life Sciences, pounds and uses thereof pending. T.W. Dubensky reports personal fees and
Harbour BioMed, Allarity Therapeutics, GI Innovation, Aulos BioScience, other from Tempest Therapeutics during the conduct of the study; in addi-
IgM BioSciences, Aptevo Therapeutics, Medikine, Sairopa, IconOVir Bio, Qur- tion, T.W. Dubensky has a patent to several TPST-1120 composition, methods
gen, Glenmark, FBD Biologics, MBrace, Astellas, BioNTech, SK Life Sciences, of use and biomarker pending and issued. S.H. Whiting reports employed
Revolution Medicines, and Multitude; personal fees from Terumo and Boxer by Tempest Therapeutics. S.V. Ulahannan reports grants from Tempest Ther-
Capital outside the submitted work; in addition, J.D. Powderly has a patent apeutics during the conduct of the study; other from Eisai Pharmaceutical,
to BioCytics is developing personalized cellular immunotherapies pending; AstraZeneca, IGM Biosciences; grants from AbbVie, Inc, Adlai Nortye, Artios
and J.D. Powderly is the founder and owner of Carolina BioOncology Insti- Pharma, ArQule, Inc, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol My-
tute PLLC (phase 1 clinic) and BioCytics Inc (Human Applications Lab), of ers Squibb, Celgene Corporation, Ciclomed LLC, Eisai Pharmaceutical, Erasca,
which both of these entities are developing intellectual property on the de- Evelo Biosciences, Inc, Exelexis, G1 Therapeutics, Inc, GlaxoSmithKline GSK,
livery of personalized cellular immunotherapies manufactured at the point of IGM Biosciences, Immunitas Therpeutics, Incyte, Isofol, Jazz Pharmaceuticals,
care. Both entities perform sponsored contract professional services for many Klus Pharma, Inc, Macrogenics, Merck Co. Inc, Mersana Therapeutics, Omega
small biotech/biopharma entities as pre-IND, IND, and CRO/CDMO consult- Therapeutics, OncoMed Pharmaceuticals, Inc, Pfizer, Purple Biotech, Rgen-
ing services. O.V. Crysler reports grants from Tempest Therapeutics during eron Pharmaceuticals, Inc, Revolution Medicines, Inc, Synermore Biologics Co,
the conduct of the study; grants from Servier Pharmaceuticals LLC, Genen- Takeda, Tarveda, Tesaro, Tempest Therapeutics, Theradex, Totos Medicines,
tech Inc, ACCRU, Surface Oncology, and AstraZeneca outside the submitted Inc, Tvardi Therapeutics, and Vigeo Therapeutics Inc outside the submitted
work. P.N. Munster reports grants from Tempest during the conduct of the work. No other disclosures were reported.
study; grants from Oric, Arvinas, Actuate, GSK, Revolution Medicine, Merck,
Xynomics, Amgen, Bliss Bio, Blueprint, IGM, Inventis BIo, Novartis, Cyteir;
other from AtlasMedex, RasCal, Catalent, and Alessa outside the submitted
work. M.A. McKean reports grants from Tempest Therapeutics during the
Authors’ Contributions
conduct of the study; grants from Aadi Biosciences, Alpine Immune Sciences, M. Yarchoan: Conceptualization, formal analysis, investigation, writing-
Arcus Biosciences, Arvinas, Ascentage Pharma Group, ASCO, Astellas, Aulos original draft, writing-review and editing. J.D. Powderly: Investigation,
Bioscience, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, writing-review and editing. B.R. Bastos: Investigation, writing-review and
Bristol Myers Squibb, C4 Therapeutics, Dragonfly Therapeutics, EMD Serono, editing. T.B. Karasic: Investigation, writing-review and editing. O.V. Crysler:
Epizyme, Erasca, Exelixis, Foghorn Therapeutics, G1 Therapeutics, Genen- Investigation, writing-review and editing. P.N. Munster: Investigation, writing-
tech/Roche, Gilead Sciences, GlaxoSmithKline, IDEAYA Biosciences, Ikena review and editing. M.A. McKean: Investigation, writing-review and editing.
Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceu- L.A. Emens: Investigation, writing-review and editing. Y.M. Saenger: In-
ticals, Jazz Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate vestigation, writing-review and editing. Y. Ged: Investigation, writing-review
BioPharma, Krystal Biotech, MedImmune, Mereo BioPharma, Metabomed, and editing. R. Stagg: Investigation, writing-review and editing. S. Smith:
NBE Therapeutics, Nektar, Novartis, NucMito Pharmaceuticals, OncoC4, On- Investigation, writing-review and editing. C.C. Whiting: Data curation, su-
corus, OnKure, PACT Pharma, Plexxikon, Poseida, Prelude Therapeutics, pervision, investigation, writing-review and editing. A. Moon: Data curation,
Pyramid Biosciences, Regeneron, Remix Therapeutics, Sapience Therapeutics, formal analysis, supervision, investigation, writing-review and editing. P. Pr-
Scholar Rock, Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, asit: Data curation, formal analysis, investigation, writing-review and editing.
Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAl- Y. Jenkins: Data curation, formal analysis, supervision, investigation, writing-
liance Biosciences, Xilio; grants and other from Moderna, Pfizer; other from original draft, project administration, writing-review and editing. N. Standifer:
Castle Biosciences, IQVIA, and Merck outside the submitted work. L.A. Emens Data curation, formal analysis, investigation, writing-review and editing. T.W.
reports grants from Tempest during the conduct of the study; grants from Dubensky: Conceptualization, supervision, funding acquisition, investigation,
Ankyra Therapeutics, AstraZeneca, Bolt Therapeutics, Bristol Myers Squibb, writing-review and editing. S.H. Whiting: Data curation, formal analy-
Compugen, CytomX, EMD Serono, Genentech, Roche, Immune Onc, Merck, sis, supervision, investigation, writing-original draft, project administration,

1108 Cancer Res Commun; 4(4) April 2024 https://doi.org/10.1158/2767-9764.CRC-24-0082 | CANCER RESEARCH COMMUNICATIONS
 PPARα Inhibition in Patients with Advanced Solid Cancers

writing-review and editing. S.V. Ulahannan: Supervision, investigation, Note

writing-review and editing.
Supplementary data for this article are available at Cancer Research Comm-
unications Online (https://aacrjournals.org/cancerrescommun/).
Acknowledgments
Received February 09, 2024; revised February 16, 2024; accepted March 27,
Editorial support was provided by Ingrid Koo, PhD, and funded by Tempest 2024; published first April 18, 2024.
Therapeutics.

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1110 Cancer Res Commun; 4(4) April 2024 https://doi.org/10.1158/2767-9764.CRC-24-0082 | CANCER RESEARCH COMMUNICATIONS