Background

A high unmet need remains for predictive biomarkers for efficacy in patients (pts) treated with immunotherapy. Here we report primary results from Parts 1 and 2 of CheckMate 592 (NCT03001882), an open-label, phase 2 trial exploring the association of biomarkers with efficacy of 1L NIVO + IPI in pts with mNSCLC.

Methods

Pts with previously untreated mNSCLC were enrolled to either Part 1 (stratified by tumor PD-L1 ≥1% and <1%) or Part 2 and received NIVO (240 mg Q2W) + IPI (1 mg/kg Q6W) until disease progression, unacceptable toxicity, or for ≤ 2 y of treatment (tx). Primary endpoints (EPs): ORR (per investigator) by baseline (BL) and on-tx biomarkers including PD-L1 expression in Part 1; ORR by BL tumor mutational burden in tissue and blood (tTMB and bTMB) in both Parts 1 and 2. Other EPs included safety and exploratory biomarker analyses. Four-gene inflammatory gene signature (CD8A, CD274, STAT-1, LAG-3) was assessed in biopsy samples at BL and on-tx by RNA sequencing.

Results

BL characteristics were generally similar between Part 1 (n = 60) and Part 2 (n = 170), and across tTMB and bTMB subgroups. At 12.5-mo minimum follow up, ORR in Part 1 was 30% and 39% in PD-L1 ≥1% (n = 30) and <1% (n = 28) subgroups, respectively. ORR by TMB (Parts 1 and 2 combined) is shown in the table. Four-gene inflammatory gene signature score showed a trend of increase on-tx (n = 17) compared to BL (n = 40) and was numerically higher in responders (complete or partial response; n = 13) vs non-responders (stable or progressive disease; n = 27); supporting data and additional efficacy results will be presented. Grade 3/4 tx-related adverse events occurred in 33% of treated pts. Table: 2MO

ORR by TMB

Conclusions

In CheckMate 592, high tTMB and bTMB were associated with better responses to 1L NIVO + IPI in pts with mNSCLC. Exploratory analyses suggest that tumor inflammation, measured by 4-gene inflammatory gene signature score, may increase with NIVO + IPI treatment.

Clinical trial identification

NCT03001882.

Editorial acknowledgement

Medical writing and editorial assistance was provided by Meenakshi Subramanian at Evidence Scientific Solutions Inc.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

S. Gettinger: Other, Personal and Institutional, Member, Member of safety committee for another BMS trial evaluating immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Thoracic Medical Oncology, Yale Comprehensive Cancer Center. M. Schenker: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, Sanofi, Regeneron, GSK, BeiGene, Astellas, Amgen, Bayer, Clovis, Gilead, Ipsen, Novartis, Pfizer, PharmaMar, Eisai, Tesaro. J. De Langen: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Boehringer, AstraZeneca; Non-Financial Interests, Institutional, Other: Merck Serono, Roche. J.R. Fischer: Financial Interests, Institutional, Research Grant: Bristol Meyers Squibb, MSD, Roche, Novartis, AstraZeneca, Sanofi, Pfizer, GSK, BeiGene, Pharma Mar, Amgen, Bayer, Gilead; Financial Interests, Institutional, Advisory Role: Bristol Meyers Squibb, MSD, Roche, Novartis, AstraZeneca, Sanofi, Pfizer, GSK, BeiGene, Pharma Mar, Amgen, Bayer, Gilead. D. Morgensztern: Financial Interests, Personal, Advisory Role: AbbVie, G1 Therapeutics, Lilly, Arcus; Financial Interests, Institutional, Research Grant: Heat Biologics, Merck, Celgene, AstraZeneca, Baxter, Incyte, Bristol Myers-Squibb, Epicentrx, Pfizer, Roche, Lilly, Altum, Array, Surface, Boehringer Ingelheim, Y-mabs. T. Ciuleanu: Financial Interests, Personal and Institutional, Other, Fee for clinical trial activities: Astelas Pharma, Janssen, Merck Sharp & Dohme, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boerigher Ingelheim, Bristol Meyers Squibb; Financial Interests, Institutional, Research Grant, PN-II-P4-ID-PCE-2020-2: University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca. T. Beck: Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb. J. De Castro Carpeno: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme; Financial Interests, Personal, Advisory Role, Consulting fees: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Jansen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche, Takeda, Sanofi; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pfizer, F. Hoffmann-la Roche, Takeda, Sanofi, Bayer. C. Schumann: Non-Financial Interests, Personal, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Other, Clinical trial: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board, Presentation and medical writing: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb. K. Deschepper: Financial Interests, Institutional, Advisory Board: Amgen Belgium, Bristol Myers Squibb, AstraZeneca, MSD Belgium. E. Nadal: Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck Serono, Roche; Financial Interests, Personal and Institutional, Advisory Role: Bristol Myers Squibb, MSD, Merck Serono, AstraZeneca, Lilly, Sanofi, Boehringer Ingelheim, Amgen, Roche, Bayer; Financial Interests, Institutional, Advisory Board: Roche, Apollomica. K. Schalper: Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Navigate Biopharma, Tesaro/GSK, Moderna Inc., Takeda, Surface Oncology, Pierre-Fabre, Merck, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer Ingelheim, Akoya Biosciences; Financial Interests, Personal and Institutional, Advisory Role: Clinica Alemana Santiago, Shattuck Labs, EMD Serono, Torque/Repertoire Therapeutics, Agenus, Genmab, OnCusp, Parthenon Therapeutics, Molecular Templates, Genmab; Financial Interests, Institutional, Invited Speaker: PeerView, Roche, Genmab, BMS, Takeda, Merck; Financial Interests, Institutional, Advisory Board: Agenus, Shattuck Labs. T. Spires: Financial Interests, Personal, Full or part-time Employment, Stock or stock options: Bristol Myers Squibb. D. Balli: Financial Interests, Personal, Full or part-time Employment, Stock or stock options: Bristol Myers Squibb. S. Karam: Financial Interests, Personal, Full or part-time Employment, Stock Options: Bristol Myers Squibb. D.R. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus, Arrys Therapeutics, Ascendis Pharma, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, Bristol Meyers Squibb, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Endeavor, Erasca, Faeth Therapeutics, FujiFilm Pharmaceuticals, G1 Therapeutics, Roche/Genentech, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, Ipsen, Janssen, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo Oncology, Lyell Immunopharma, MacroGenics, MedImmune, Merck, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, SeaGen, Shenzhen Chipscreen Biosciences, Synthekine, Taiho, Tango Therapeutics, Tarveda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Zai Laboratory; Financial Interests, Institutional, Advisory Role: AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMD Serono, Evidera, GlaxoSmithKline, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Novocure, Pfizer, Pyxis Oncology, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi-Aventis. All other authors have declared no conflicts of interest.

Background

SNPs of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T cell priming, are associated with auto- and allo-immunity. Previously, studies implied a role for these SNPs as surrogate markers for outcome in melanoma patients treated with immune checkpoint inhibitors. However, no predictive SNPs are defined to date. The primary aim of this study was to analyze different CTLA-4 SNPs in a large real-world cohort of melanoma patients treated with ipilimumab and to correlate these SNPs with toxicity and survival.

Methods

Archival blood and/or tumor-tissue samples were collected from 317 advanced stage melanoma patients treated with ipilimumab (+/- nivolumab) in 5 Swiss and Dutch hospitals. DNA was extracted and used for MALDI-TOF MS based genotyping for 11 different SNPs. Associations between different allele genotypes and occurrence of grade ≥3 toxicity, treatment response and survival outcomes were tested using univariable logistic regressions or Cox proportional hazard models.

Results

DNA of 216/317 patients could be analyzed. The cohort was representative of a real-life population of metastatic melanoma patients receiving ipilimumab (+/- nivolumab): among the remaining 216/317 evaluable patients, 65.3% were male, median age at diagnosis was 59 years, 37% of patients had partial or complete response and 59% had ≥1 immune-related adverse events. A TT-genotype in the -1722 C/T SNP (rs733618, T=0.8345 (1000Genomes)), located in the promoter region of CTLA-4, was significantly associated with a decreased rate of ≥ grade 3 toxicity [odds ratio=0.40; CI₉₅=0.16 - 1.00; p=0.049]. The TT-genotype in the Jo27 T/C SNP (rs11571297, T=0.5575 (1000Genomes)) [hazard ratio (HR)=0.54; CI₉₅=0.28-1.02, p=0.056] and the GG-genotype in the Jo31 SNP (rs11571302, G=0.5713 (1000Genomes) [HR=0.54; CI₉₅ = 0.29-0.99, p=0.046], both located at the 3’ untranslated region, were associated with increased overall survival.

Conclusions

CTLA-4 SNPs might be predictive of toxicity and/or survival in melanoma patients receiving ipilimumab. Confirmatory studies are needed to exploit findings of this exploratory study and to investigate the exact role of CTLA-4 SNPs as possible biomarkers.

Legal entity responsible for the study

The authors.

Funding

BMS.

Disclosure

K.D. Joode: Financial Interests, Personal, Other, Travel expenses congress: Ipsen. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi. R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Licensing Fees, Patent pending: Pamgene; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. Y. Metaxas: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

In the clinic, immune checkpoint immunotherapy (ICI) is used to re-activate immune reactions against tumor neoantigens, leading to striking remission in cancer patients’ tumors. However, complete or durable responses to ICI treatment only occur in a minority of patients. While the level of tumor mutational burden (TMB) can be used as a predictive marker for responsiveness, we questioned whether the subcellular localization of the neoantigens within the tumor cell additionally plays a role. Using 3 human datasets with 1722 patients treated with ICI, we previously highlighted that patients bearing a high proportion of tumor neoantigens at the membrane of cancer cells responded better to anti-PD1. To decipher underlying immunological mechanisms, we developed a melanoma mouse model that expresses membrane-bound or soluble antigens and analyzed local and systemic anti-tumor immune responses upon anti-PD1 immunotherapy.

Methods

We engineered B16F10 melanoma cells to express membrane-bound or soluble OVA and analyzed intratumoral immune cell infiltration upon implantation in C57BL6 mice. We then compared tumor growth upon anti-PD1 treatment in the wild-type mice or in mice depleted for specific immune cells population. In addition, we compared systemic responses upon tumor implantation via ex vivo antigen-specific restimulation of the splenocytes.

Results

We demonstrated that mice bearing tumors with membrane-bound OVA have increased local and systemic anti-tumor immune reactions compared to soluble OVA, which rendered these tumors highly susceptible to ICI, leading to complete tumor rejection in mice. We additionally observed that tumor rejection was dependent on the level of antigen expressed in the cancer cells, with an increased rejection rate observed for the high dose membrane-bound OVA tumors compared to low ones. We surprisingly found that tumor rejection was independent of immunoglobulin G (IgG), of NK cells and of BatF3⁺ cross-presenting dendritic cells, and mostly relied on CD8⁺ T cells cytotoxicity, and partially on CD4⁺ T cells.

Conclusions

In this study, we show that the subcellular localization of tumor neoantigens plays an important role in the immunogenicity of tumors and subsequent responsiveness to anti-PD1 immunotherapy.

Legal entity responsible for the study

Priscilla S. Briquez, Jeffrey A. Hubbell.

Funding

This work was funded by the Chicago Immunoengineering Innovation Center of the University of Chicago and NIH R01CA219304 (to M.A.S).

Disclosure

All authors have declared no conflicts of interest.

Background

HCC has a mortality/morbidity ratio of 0.98 and a five-year survival rate of only about 5%-6%, indicating a very poor prognosis. Nivolumab is a programmed death receptor-1 (PD-1) inhibitor. H101, an E1B gene deleted oncolytic adenovirus, is known to have significant antitumor activity. In addition, local injection of H101 might enhance the effect of antitumor therapies (chemotherapy and radiotherapy). We report on the safety and efficacy of H101 in combination with nivolumab in patients (pts) with advanced HCC.

Methods

This single-arm, phase II study enrolled pts with HCC who failed prior systemic therapy. The combined treatment period starts from day 8, which will be recorded as the first cycle. Eligible pts received i.v. H101 (2 vials, on day 8) and i.v. nivolumab (3mg/kg, on day 9) followed by every 2 weeks. While H101 could be injected once every 4 weeks or suspended, depending on the percentage of CD8+ lymphocytes. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or the physician’s decision. . The primary endpoint was objective response rate (ORR) per RECIST v1.1. and 6-month OS% was the other co-primary endpoint. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), safety and exploratory bioinformatics analysis.

Results

Up to Mar 2022, 21 pts were enrolled in cohorts. Of 18 evaluable pts, confirmed ORR and DCR were 11.1% and 38.9% respectively, with 2 partial responses (PR) and 5 stable diseases (SD), and 6-month OS% was 77.8%. Median PFS was 2.27 months [95% confidence interval (CI), 1.44-3.09], median OS was 15.04 months [95% CI, 8.33-21.76] and median DOR was 6.51 months. The most common treatment-emergent adverse events (TEAEs) in all pts were low-grade fever (90%) and pain related to centesis (60%). No grade 4/5 adverse events were reported.

Conclusions

H101 in combination with nivolumab showed promising activity with well-tolerated toxicities in pts with advanced HCC. Updated results will be presented.

Clinical trial identification

MIT-003 Institutional)/CA209-7CE (BMS).

Legal entity responsible for the study

Z. Meng.

Funding

Bristol Myers Squibb.

Disclosure

All authors have declared no conflicts of interest.

Background

EBV is associated with NPC, with the virus in a latent state. Nstat is a Class-I selective oral HDAC inhibitor that induces expression of the lytic BGLF4 EBV protein kinase in EBV⁺ tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-mediated inhibition of viral and cellular DNA synthesis and apoptosis. Nstat plus VGCV (oral prodrug of GCV) showed a favorable safety profile with anti-tumor activity in a phase 1b/2 study in R/R EBV⁺ lymphoma (recommended phase 2 dose [RP2D]: Nstat 20 mg daily [QD], 4 d/wk + VGCV 900 mg QD). Here, phase 1b uses a 3+3 dose escalation for Nstat + VGCV RP2D selection in RM-NPC, followed by an expansion at the RP2D in other EBV⁺ solid tumors. In phase 2, up to 60 RM-NPC pts will be randomized 1:1 to receive Nstat + VGCV at the RP2D +/- PEM. Herein we report preliminary safety results from phase 1b in RM-NPC (NCT05166577).

Methods

Pts aged ≥18 with EBV⁺ RM-NPC (1-3 prior therapies) with measurable disease (RECIST v1.1) and no curative options receive daily Nstat 20-40 mg 4d per wk with VGCV 900-1800 mg daily in phase 1b. Primary endpoints are incidence of dose limiting toxicities (DLTs) (phase 1b) and overall response rate (phase 2); secondary endpoints include duration of response, disease control rate, progression free survival and overall survival. Responses are assessed per RECIST v1.1 from week 8.

Results

As of 15-Sept-22, 7 male pts (median age 51y [19-61y]) were enrolled; 3 in dose level (DL) 1 and 4 in DL2 received Nstat 20 and 30 mg QD, respectively, 4 d/wk, plus VGCV 900 mg QD. Median no. prior systemic therapies was 2; all pts were refractory to last therapy with bone (6/7), liver (5/7), and lung (3/7) metastases. Related AEs were all G1-2, most commonly fatigue, nausea, and increased creatinine (n=3 each); no G3+ AEs/DLTs and 1 SAE (cancer pain) were reported. Of 6 pts evaluable for response, 2 had SD (with decreasing/stable plasma EBV DNA, pEBVd); 4 had PD (with rising pEBVd).

Conclusions

The combination of Nstat and VGCV represents a novel approach for the treatment of EBV⁺ NPC and is tolerated at doses exceeding the RP2D for lymphoma. Dose escalation continues.

Clinical trial identification

NCT05166577.

Legal entity responsible for the study

Viracta Therapeutics.

Funding

Viracta Therapeutics.

Disclosure

L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Oncorus, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Janpix, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Invited Speaker: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Astellas, Bayer, Amgen, Symphogen, Intensity Therapeutics, Shattucks, EMD Serono; Non-Financial Interests, Personal, Advisory Role: ICR. D.W. Lim: Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, MSD, Pfizer, Novartis; Financial Interests, Institutional, Invited Speaker: Roche, Novartis; Financial Interests, Institutional, Invited Speaker, Grant funding for investigator-sponsored study: Bristol Myers Squibb. S.A. Khan: Financial Interests, Personal, Advisory Board, I conduct molecular tumor boards for FMI: Foundation Medicine; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Eisai; Financial Interests, Personal, Other, give educational lectures to oncologists about molecular testing: Roche Pakistan. P.J. Voon: Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck Sharp & Dohme, Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Ipsen; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Novartis, Boehringer Ingelheim, Janssen-Cilag, Johnson & Johnson, Viracta Therapeutics Inc, Roche, Merck KGaA, Merck Sharp & Dohme. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daichi Sankyo. A. Elguindy, A. Katkov, L. Rojkjaer, Y. Katz: Financial Interests, Personal, Full or part-time Employment: Viracta Therapeutics. B.B.Y. Ma: Financial Interests, Personal, Invited Speaker, Advisory Board/Consultancy: Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board, Consultancy: Y-biologics, Boehringer Ingelheim, Merck Serono; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board and consultancy: Viracta Therapeutics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Merck Serono; Financial Interests, Institutional, Research Grant, Research Grant Preclinical: Novartis. All other authors have declared no conflicts of interest.

Background

Stage III non-small cell lung cancer (NSCLC) is highly heterogeneous with great variations in clinical practice. Though neoadjuvant immunotherapy plus chemotherapy significantly improved pCR and EFS in resectable NSCLC patients compared with chemotherapy alone in previous study, the evidence in stage III NSCLC are limited. This is the first study to evaluate durvalumab neoadjuvant/adjuvant in stage III NSCLC patients.

Methods

A prospective phase II, single-arm study enrolled the patients (according to the MDT) with histologically confirmed stage IIIa-IIIc NSCLC without known EGFR/ALK mutations. Patients received neoadjuvant durvalumab (1500mg) plus platinum-based chemotherapy q3w for 2-4 cycles followed by surgery, then adjuvant durvalumab mono q4w for 12 cycles. The primary endpoint was MPR (≤10% viable tumor cells). Secondary endpoints included pCR (0% viable tumor cells), ORR, DFS, OS, and safety. Predictive biomarkers was exploratory endpoint.

Results

From February 7, 2021 to May 30, 2022, a total of 14 patients were enrolled with median follow-up of 9.5 months. The median age was 64.5 and 71.4% were squamous carcinoma histology. The number of patients with stage IIIa, IIIb, IIIc were 2 (14.3%), 10 (71.4%) and 2 (14.3%), respectively. All patients completed neoadjuvant therapy, 6 patients received 3 cycles and 8 patients received 4 cycles. Currently, the ORR was 64.3% (9/14), 10 patients underwent surgery, 4 patients were ineligible for surgery due to 2 with unresectable stage IIIc disease, 1 with tumor wrapping around the right bronchus and 1 with poor lung function. Among 10 resected patients, 50.0% achieved MPR and 20.0% achieved pCR. The TCR clone counts after 1 cycle neoadjuvant therapy was positively corelated with imaging regressions (p=0.044). The median DFS was not reached. Grade 3 or 4 treatment-related adverse events rate was 14.3%.

Conclusions

The results suggest that stage IIIa-IIIb NSCLC can benefit from neoadjuvant Durvalumab plus chemotherapy. Two stage IIIc patients failed to convert from neoadjuvant therapy. TCR diversity is positively correlated with imaging regression, analysis of its correlation with survival outcomes is ongoing.

Clinical trial identification

NCT04897386.

Legal entity responsible for the study

X. Dong.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

There is an urgent need to improve the safety and efficacy of immunotherapy, which has focused primarily on the adaptive immune system. Macrophages are the most common infiltrating immune cells in tumors and they can be directed to kill cancer cells by targeting macrophage-specific immune checkpoints, such as the CD47/SIRPa axis. CD47 serves as a “don’t eat me” signal on cancer cells and binds to SIRPa on macrophages to inhibit phagocytosis. Cytokines can influence macrophage polarization states, but how cytokines influence macrophage activation, particularly in the setting of macrophage checkpoint blockade, remains unknown.

Methods

To study how cytokines modulate macrophage anti-tumor function, we conducted an unbiased screen of 113 recombinant human cytokines using a novel co-culture assay that measures long-term interactions between primary human macrophages and human cancer cells. We tested how each cytokine alters macrophage-mediated cytotoxicity at baseline or in the presence of CD47 blockade. In validation studies, we tested more generally if candidate cytokines could enhance the macrophage response to tumor-opsonizing antibodies such as cetuximab (anti-EGFR mAb). We also confirmed the cross-species relevance of these findings in a murine in vitro system.

Results

Surprisingly, we found that despite not having single-agent activity, interleukin 10 (IL-10) synergizes with anti-CD47 therapy to enhance human macrophage anti-tumor function in long-term co-culture with non-small cell lung cancer (NSCLC) cells. These findings were conserved in a murine model of NSCLC in vitro. IL-10 also synergizes with tumor opsonizing antibodies, such as cetuximab, to enhance macrophage killing of cancer cells. IL-10 priming of macrophages enhanced antibody-dependent phagocytosis of multiple cancer cell lines, likely underlying its mechanism of action.

Conclusions

We discovered an unexpected role for IL-10 in enhancing macrophage anti-tumor functions in response to CD47 blockade and tumor-opsonizing antibodies. These findings illuminate a novel strategy to harness macrophages for cancer immunotherapy and provides preclinical rationale for testing this therapeutic combination in patients with cancer.

Legal entity responsible for the study

The authors.

Funding

Whitehead Institute.

Disclosure

A. Maoz: Non-Financial Interests, Personal, Other, Patent application: Whitehead Institute. K. Vaccaro: Financial Interests, Personal, Full or part-time Employment: DEM Biopharma; Financial Interests, Personal, Stocks/Shares: Orchard therapeutics. K. Weiskopf: Financial Interests, Personal, Advisory Board, Scientific co-founder, SAB member, equity ownership, royalties: ALX Oncology; Financial Interests, Personal, Advisory Board, Scientific co-founder, SAB member, equity ownership, royalties, compensation: DEM Biopharma; Financial Interests, Personal, Other, Scientific advisor, compensation: Carisma Therapeutics; Financial Interests, Personal, Stocks/Shares: Adaptimmune, Gingko Bioworks, Guardant Health, Immunity Bio, Myovant Sciences, Arbutus Biopharma, Arvinas Inc, Beyond Air, Biomarin Pharmaceutical Inc, Trillium Therapeutics, Bluebird Bio, Medicenna Therapeutics, Kura Oncology, Sesen Bio; Financial Interests, Personal, Royalties, Patents, royalties, and licensing fees: Stanford University; Financial Interests, Personal, Other, Patent applications, anticipated royalties and licensing fees: Whitehead Institute; Financial Interests, Personal, Invited Speaker, Royalties and licensing fees: Gilead Sciences, Inc; Financial Interests, Personal and Institutional, Research Grant: AACR-AstraZeneca Career Development Award for Physician-Scientists, in Honor of José Baselga. All other authors have declared no conflicts of interest.

Background

Combination of chemotherapy (CT) with PD-1 blockade is a front-line treatment for lung cancer. Our aim was to explore CT effects on CD8 T cells that proliferate in response to concomitant PD-1 blockade.

Methods

To reproduce the exhausted immune landscape of cancer, we used a well-established murine model of chronic lymphocytic choriomeningitis virus (LCMV) infection. At day 45 post-infection, mice were assigned to 4 treatment groups (untreated, CT, aPD-L1, combo). The CT regimen consisted of cisplatin (2.5 mg/kg) and pemetrexed (300 mg/kg). CT and aPDL1 were given every 3 days for 2 weeks. This regimen was tested also in the syngeneic CT26 tumor model and T cell phenotyping was performed after 4 doses (day 20 post-tumor implantation).

Results

In the LCMV model, LCMV-sp CD8 T cells in lymphoid and non-lymphoid tissues were lower in the combo vs aPD-L1. Proliferation of LCMV-sp CD8 T cell was higher in combo than in chemo and untreated, but lower than in aPD-L1. Frequency of stem-like LCMV-sp CD8 was higher in chemo group vs the others, with no differences in absolute numbers. The effector subsets, both the transitory and terminally differentiated, were more vulnerable, resulting in decreased IFN-g production and viral control in the combo compared to the aPD-L1 group. In the tumor model, CT and/or aPD-L1 delayed tumor growth. Compared to the untreated group, tumor infiltrating Ag-sp and PD-1+ CD8 T cells were significantly higher not only in the aPD-L1 and combo groups, but also in the chemo group. Though non-significant, frequency of proliferating Ag-sp CD8 T cells was lower in combo vs aPD-L1 group. Frequency of stem-like cells was low, without significant differences across groups.

Conclusions

Chemotherapy attenuates the proliferation of effector cells mediated by concomitant PD-1 blockade. The preservation of the stem-like subset, that provide the proliferative burst needed for an effector T cell response, suggests that chemotherapy toxicity on CD8 T cells is likely transient and reversible after discontinuation of chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Emory University, Emory Vaccine Center.

Disclosure

S. Novello: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Eli Lilly, Novartis, Beigene, Amgen; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen; Financial Interests, Institutional, Invited Speaker, IIT: MSD, BI; Non-Financial Interests, Personal, Leadership Role, president of this european advocacy: WALCE. G. Scagliotti: Financial Interests, Personal, Other, Honoraria/Consultant: AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, J&J, Takeda, BeiGene, Bayer. S.S. Ramalingam: Financial Interests, Institutional, Other, Consultant: Amgen, BMS, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, GSK; Financial Interests, Personal, Other, Editor in Chief, Cancer journal: American Cancer Society; Financial Interests, Personal, Research Grant: Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. R. Ahmed: Other, Personal, Other, patent: Anti-PD-1 monoclonal antibodies; Other, Personal and Institutional, Funding, research fundings: Merck. All other authors have declared no conflicts of interest.