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- Inge-Marie Svane (Herlev, Denmark)
- Alessandra Curioni (Zurich, Switzerland)
729MO - Final results of the first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in combination with nivolumab in subjects with solid tumors relapsed/refractory to prior anti-PD1/PD-L1 treatment
- Ignacio Melero (Pamplona, Spain)
Abstract
Background
Growth and differentiation factor 15 (GDF-15) is a major tumor-derived immunosuppressant. Tumoral expression correlates with poor clinical outcome [Front Imm 2020 May 19;11:951]. Here we present the results of the first-in-human, phase 1 trial of the GDF-15 neutralizing antibody CTL-002.
Methods
This was the first-in-human, phase 1 dose escalation clinical trial of CTL-002 given IV as monotherapy and in combination with nivolumab in subjects with advanced-stage solid tumors relapsed/refractory to at least one prior anti-PD-1/PD-L1 therapy and having exhausted all available therapeutic options. 25 subjects received escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in an integrated monotherapy-followed-by-combination-design with one cycle CTL-002 followed by combo with nivolumab.
Results
The combination of CTL-002 and nivolumab showed excellent tolerability, no DLT and Grade ≥ 4 AE occurred. A substantial tumor-selective influx of CD8+ and CD4+ T cells was detected in most patients under treatment, and significant increases in proliferating and cytotoxic (CD3+GrzB+) T cells in tumor tissue. Five patients relapsed/refractory to prior anti-PD1/PD-L1 treatment and with all other available treatment options exhausted experienced tumor regression, three of them as confirmed, lasting partial responses (> 8 months and ongoing; HCC, CUP tumor and Mesothelioma), others experienced prolonged stable disease.The tumor regression rate observed at dose level 4+5 was 25%. Biomarker-analyses identified a marker that was present in ∼25% of patients and if employed for patient selection would have resulted in a 50% partial response rate and a clinical benefit rate of > 65% in this heavily pre-treated, last-line mixed solid tumor population.
Conclusions
CTL-002 neutralization of GDF-15 in combination with PD-1 blockade was safe, increased CD8+ and CD4+ T cell tumor infiltration and antitumoral activity and induced confirmed objective clinical responses and lasting tumor regression in heavily pre-treated and previously anti-PD-1/-PD-L1 relapsed/refractory patients at a rate of 25% for dose level 4 and 5. Phase 2 development is ongoing.
Clinical trial identification
NCT04725474.
Legal entity responsible for the study
Catalym GmbH.
Funding
Catalym GmbH.
Disclosure
I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, Noxxon Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche; Financial Interests, Personal, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator; Financial Interests, Personal, Advisory Role: Catalym. M.J. De Miguel: Financial Interests, Personal, Advisory Role: Syneos, Janssen, MSD; Financial Interests, Institutional, Principal Investigator: AbbVie, Array, Achilles, Basilea, Bayer, Biontech, Faron, MSD, Novartis, Cytomex, Genentech, Genmab, Janssen, Menarini, Nektar, Catalym, Regeneron, Zenith. M. Goebeler: Financial Interests, Personal, Gemoab, BMS, Janssen, Roche, Pfizer, Novartis, Catalym. E. Calvo: Financial Interests, Personal, Full or part-time Employment, Medical Oncologist, Clinical Investigator; Director, Clinical Research: START, HM Hospitales Group; Financial Interests, Personal, Advisory Role: Nanobiotix, Janssen, Roche / Genentech, Amcure, TargImmune, Servier, BMS, PharmaMar, Alkermes, Amunix, Adcendo, Anaveon, AstraZeneca, MonTa, MSD, Nouscom, Novartis, OncoDNA, Sanofi, Syneos Health, T-Knife, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: BeiGene, Achilles; Non-Financial Interests, Personal, President and founder: Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences); Financial Interests, Personal, Ownership Interest: START corporation, Oncoart Associated, International Cancer Consultants; Financial Interests, Personal, Scientific Board: Adcendo, Chugai Pharmaceuticals, PsiOxus Therapeutics; Financial Interests, Personal, IDMC Steering Committee: BeiGene; Non-Financial Interests, Personal, IDMC Chair: EORTC ; Financial Interests, Personal, Steering Committee: MedSIR, Novartis. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Myers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. R. Dummer: Financial Interests, Personal, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. C.M. Sayehli: Non-Financial Interests, Personal and Institutional, Principal Investigator: Amgen, Bayer, BMS, Boehringer Ingelheim, Chugai, Glenmark; Personal, Travel Support, Congress Fees, Hotel Costs: Novartis, Lilly, BMS, Celgene. M.F. Sanmamed: Financial Interests, Personal, Consultancy: Numab; Financial Interests, Personal, Advisory Role: Pieris; Financial Interests, Personal, Invited Speaker: MSD, BMS; Financial Interests, Personal, Project Research: Roche; Financial Interests, Institutional, Clinical Trial: Roche, BMS, Amgen, Genmab, Genentech, Replimune; Non-Financial Interests, Personal, Advisory Role: ASEICA (Spain). M.H.H. Schuler: Financial Interests, Personal, Invited Speaker: Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Roche; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca; Non-Financial Interests, Principal Investigator, Member, Study Steering Board: Janssen. P. Fettes: Financial Interests, Personal, Full or part-time Employment, Head of Clinical Operations: CatalYm; Financial Interests, Personal, Stocks/Shares: CureVac. K. Klar: Financial Interests, Personal, Full or part-time Employment: CatalYm. C. Schuberth-Wagner: Financial Interests, Personal, Scientific Advisor: Lodo Therapeutics LTD; Financial Interests, Personal, Full or part-time Employment: Rigontec GmbH, CatalYm GmbH; Financial Interests, Personal, Stocks/Shares: Rigontec GmbH, CatalYm GmbH; Financial Interests, Personal, Inventor: Rigontec GmbH, CatalYm GmbH. J. Wischhusen: Financial Interests, Personal: CatalYm GmbH, Aeterna Zentaris Inc.; Financial Interests, Personal, Stocks/Shares, founder shares: CatalYm GmbH; Financial Interests, Personal and Institutional, All payments go to the University which then distribute a proportion to the inventors.: CatalYm GmbH, Aeterna Zentaris Inc., Argenx; Financial Interests, Personal, Funding: CatalYm GmbH, Aeterna Zentaris Inc., Argenx. E. Leo: Financial Interests, Personal, Affiliate: Catalym GmbH; Financial Interests, Personal, Stocks/Shares: Catalym GmbH. All other authors have declared no conflicts of interest.
730MO - First-in-human phase I study of INCAGN02390, a TIM-3 monoclonal antibody antagonist in patients with advanced malignancies
- Martin Gutierrez (Hackensack, United States of America)
Abstract
Background
TIM-3 is a transmembrane checkpoint receptor expressed on multiple immune cells that promotes an inhibitory tumor microenvironment. INCAGN02390 is a fully human Fc-engineered IgG1κ monoclonal antibody that selectively inhibits TIM-3 ligand interactions. This study is primarily aimed to determine the safety and tolerability and define the MTD or PAD of INCAGN02390 monotherapy.
Methods
This is a phase 1, multicenter, open-label, dose-escalation study that enrolled pts with locally advanced or metastatic solid tumors that failed available therapies, were intolerant to treatment, or refused noncurative standard treatment. A 3+3 dose-escalation design was used; pts received intravenous INCAGN02390 Q2W in 7 dose levels (DLs): 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. The primary endpoint was safety and tolerability. Other endpoints were PK, PD and preliminary efficacy per RECIST v1.1.
Results
Forty pts (median age, 63 y) were enrolled; 53% were male and 83% had ECOG PS 1. Lead cancer types were breast (15%), lung (13%), and colorectal (10%). 98% received prior systemic therapy (58% had prior immunotherapy). No DLT was observed and MTD was not reached. Most frequent treatment-emergent adverse events (TEAEs) were anemia (35%), back pain (30%), and fatigue (28%). Drug-related grade ≥3 TEAEs were observed in 7.5% of pts (anemia, adrenal insufficiency, and amylase increased [n=1 each]; all Gr3). One drug-related serious TEAE (adrenal insufficiency) occurred at the 1600 mg DL. One drug-unrelated fatal TEAE (multi-organ failure) occurred in the 800-mg DL. INCAGN02390 trough serum concentrations achieved steady state around Cycles 4 to 6. Maximum concentration and area under the serum concentration-time curve were linear across most DLs. Doses ≥400 mg led to trough TIM-3 receptor occupancy levels of ≥90% in peripheral blood. Disease control rate was 17.5%, with 1 confirmed partial response in a pt with an adenoid cystic carcinoma in lung.
Conclusions
INCAGN02390 monotherapy was generally well tolerated, with linear PK. The 400 mg Q2W dose is selected for further investigation in phase 1b/2 studies in combinations with other immunotherapies (NCT04370704, NCT05287113).
Clinical trial identification
NCT03652077.
Editorial acknowledgement
Writing assistance was provided by Cory Pfeiffenberger, PhD (ICON, Blue Bell, PA, USA), and was funded by Incyte Corporation.
Legal entity responsible for the study
Incyte Corporation.
Funding
Incyte Corporation.
Disclosure
M.E. Gutierrez: Financial Interests, Institutional, Funding: Incyte. S. Tang: Financial Interests, Institutional, Funding: Incyte. J.D. Powderly: Financial Interests, Personal, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic.: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, STEMCELL Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: PIOMA; Financial Interests, Personal and Institutional, Invited Speaker, Also funding for contract laboratory services: Nuvation; As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc.. A.S. Balmanoukian: Financial Interests, Personal, Speakers Bureau: BMS, Genentech, AstraZeneca; Financial Interests, Institutional, Sub-investigator on the industry sponsored trial at our institution.: BMS; Financial Interests, Institutional, Sub-investigator on the industry sponsored trial at our site. No direct compensation.: MedImmune; Financial Interests, Institutional, Sub investigator on the industry sponsored trial at our site.: Regeneron; Financial Interests, Institutional, Both PI and Sub-I on Seattle Genetics trials at our site.: Seattle Genetics; Financial Interests, Institutional, sub-I on industry sponsored trial at our site: Pfizer; Financial Interests, Institutional, sub-I on industry sponsored trial at out site: Nextcure; Financial Interests, Institutional, Other, sub-I on industry sponsored trial at our site: Incyte, Rubius Therapeutics; Financial Interests, Institutional, Sub-I on industry sponsored study at our site: TAIGA therapeutics, Treadwell Therapeutics, Tyrnovo, Mereo Biopharma, Surface therapeutics, Tmunity; Financial Interests, Institutional, Invited Speaker, Both PI and sub-I on GSK sponsored trials at our site: GSK; Financial Interests, Institutional, sub-I on industry sponsored trials at our site: Epizyme; Financial Interests, Institutional, Invited Speaker, Both PI and sub-I on Arcus sponsored trials at our site: Arcus; Financial Interests, Institutional, Sub-I on industry sponsored trials at our site: amgen. J. Janik: Financial Interests, Personal, Full or part-time Employment: Incyte. P. Hoyle: Financial Interests, Personal, Full or part-time Employment: Incyte. W. Wei: Financial Interests, Personal, Full or part-time Employment: Incyte. X. Gong: Financial Interests, Personal, Full or part-time Employment: Incyte. O. Hamid: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Advisory Board: Aduro, Akeso, Amgen, Beigene, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, Seagen, Tempus, Zelluna, Bioatla, Alkermes, Instil Bio, Iovance; Financial Interests, Institutional, Invited Speaker: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, Seagen, Torque, Zelluna, Rubius.
731MO - A phase I trial of the bifunctional EGFR/TGFβ fusion protein BCA101 alone and in combination with pembrolizumab in patients with advanced solid tumors
- Glenn J. Hanna (Boston, United States of America)
Abstract
Background
BCA101 is a first-in-class bifunctional fusion protein consisting of an anti-EGFR mAb and TGFβ receptor 2 extracellular domain. Herein, we report the safety, PK/PD, and preliminary efficacy data of BCA101 as monotherapy and in combination with pembrolizumab among pts with advanced solid tumors refractory to standard therapies.
Methods
Pts received BCA101 as a single agent (SA) or in combination with pembrolizumab at escalating doses in a parallel 3+3 design starting at 64 mg IV qw; and at 240 mg IV qw with pembrolizumab 200 mg IV q3w. Primary endpoint: safety and tolerability; DLT period: 21 days. Secondary: ORR, PK/PD, PFS, and changes in plasma and intra-tumoral TGFβ signaling assessed by SMAD2 phosphorylation.
Results
As of 07-Apr-2022, 60 pts received BCA101. Forty-five pts (colorectal, n=14; pancreatic, n=7; head and neck squamous cell carcinoma [HNSCC], n=6) received SA BCA101 at doses up to 1500 mg IV weekly. Fifteen pts (SCC of the anal canal [SCAC], n=8; HNSCC, n=7) received BCA101 doses from 240 to 1500 mg IV qw in combination with pembrolizumab. MTD has not been reached. Most common AEs attributed to BCA101 include rash (72%), fatigue (30%), pruritis (20%), and epistaxis (17%); all G2 or less. One DLT observed at the 1250 mg SA dose (G3 anemia, hematuria). No drug-related G4 AEs or deaths observed. One partial response (PR) and 13 (33%) stable disease (SD) observed in 40 evaluable SA pts. In combination, PR observed in 4/13 (31%) evaluable pts (2 in SCAC, 2 in HNSCC) and a DCR of 9/13 (69%). All 4 responders have been on study >4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab. Saturation of the EGFR target was observed at BCA101 doses ≥750 mg. Dose proportional increase in Cmax and AUC observed in doses of BCA101 750-1500 mg. Prolonged neutralization of plasma TGFb1 achieved at all doses ≥500 mg. Among paired tumor biopsies (n=23), pSMAD2 reduction up to 62% was observed at doses ≥500 mg.
Conclusions
BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. Expansion cohorts for HNSCC, SCAC and cutaneous SCC are currently ongoing and results will be updated and further presented at the congress.
Clinical trial identification
NCT04429542.
Legal entity responsible for the study
Bicara Therapeutics, Inc.
Funding
Bicara Therapeutics, Inc.
Disclosure
G.J. Hanna: Financial Interests, Personal, Advisory Board: Bicara, Bio-Rad, Boxer Capital, Bristol Myers Squibb, Exicure, General Catalyst, Kura Oncology, Maverick, Merck, Naveris, Prelude, Rain Therapeutics, Regeneron, Remix, Sanofi Genzyme, SIRPant; Financial Interests, Personal, Invited Speaker: Coherus; Financial Interests, Personal, Expert Testimony: Aaronson Rappaport Feinstein & Deutsch, LLP, Ahmuty, Demers, & McManus, Esqs, Wilson Elser Moskowitz Edelman & Dicker, LLP; Financial Interests, Personal, Full or part-time Employment: Dana-Farber Cancer Institute; Financial Interests, Institutional, Research Grant: ACCRF, Repertoire, V Foundation; Financial Interests, Institutional, Funding: Actuate Therapeutics, ASCO Conquer Cancer Foundation, Bicara, Bristol Myers Squibb, Elevar, Exicire, Gateway for Cancer Reserach, Genentech, GSK, Kartos, Kite Pharma, KSQ Therapeutics, Kura Oncology, NantKewst/Altor Bioscience, Regeneron, Sanofi Genzyme, Secura Bio. A. Hernando Calvo: Award: Novartis. V. Morris: Financial Interests, Personal, Invited Speaker: Imedex LLC; Financial Interests, Personal, Advisory Board: Bicara; Financial Interests, Personal, DMC member: Incyte; Financial Interests, Institutional, Invited Speaker: Bicara; Financial Interests, Institutional, Funding: Pfizer, Bristol Myers Squibb, BioNTech, Novartis, EMD Serono. R.D. Carvajal: Financial Interests, Personal, Advisory Role: Merck, Aura Biosciences, Castle Biosciences, Immunocore, PureTech, Sorrento Therapeutics, Chimeron Bio, Rgenix, InxMed, Pierre Fabre, TriSalus Life Sciences, Iovance Biotherapeutics, Oncosec, Regeneron, Genzyme, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb /Medarex, Corvus Pharmaceuticals, IDEAYA Biosciences, Mirati Therapeutics, Novartis, Pfizer, Plexxikon, Roche/genentech; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb /Medarex; Financial Interests, Institutional, Funding: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceuticals, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Immunocore, Incyte, Macrogenics, Mirati, Novartis, Pfizer, Plexxikon, Roche/genentech, Array BioPharma, IDEAYA Biosciences, Regeneron. P.K. Paik: Financial Interests, Personal, Advisory Board: Xencor, Mirati, EMD Serono; Financial Interests, Personal, DSMC: Takeda; Financial Interests, Personal, Consulting: Novartis; Financial Interests, Invited Speaker: EMD Serono, Bicara. D.P. Zandberg: Financial Interests, Personal, Advisory Board: Blueprint Medicines, Prelude Therapeutics; Financial Interests, Personal, Advisory Role: Macrogenics; Financial Interests, Institutional, Principal Investigator: Merck, BMS, AstraZeneca, GlaxoSmithKline, Aduro, Astellas, Macrogenics, Lilly, Bicara Therapeutics, Checkmate Pharma, Novasenta. J. Kaczmar: Financial Interests, Personal, Advisory Role: Bicara Therapeutics, Inc, Rakuten Medical, Coherus Biosciences; Financial Interests, Personal: Triangle Insights Group. L. Niculescu: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics. R. Reiners: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics. D. Bohr: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics, Inc. E. Gharakhani: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics, Inc. . R. Salazar: Financial Interests, Personal, Full or part-time Employment: Bicara Therapeutics, Inc. . P.L. Bedard: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Invited Speaker, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND CommitteeMember, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. All other authors have declared no conflicts of interest.
Invited Discussant 729MO, 730MO and 731MO
- Inge-Marie Svane (Herlev, Denmark)
732MO - The combination of ICT01, a γ9δ2 T cell-activating mAb, plus pembrolizumab induces a broad antitumor immune response and disease control in patients with CPI-failure melanoma, NSCLC and bladder cancer: EVICTION trial
- Stephane Champiat (Villejuif, France)
Abstract
Background
ICT01, an anti-BTN3A mAb, activates γ9δ2 T cells that orchestrate a robust antitumor immune response of the innate and adaptive immune systems that leads to solid tumor infiltration of γ9δ2 T cells, CD8 T cells, and NK cells. (ESMO 2021, #9580) This immune-remodeling by ICT01 when combined with pembrolizumab unleashes the newly-activated, PD-1 expressing γ9δ2 and CD8 T cells that provide a novel, complementary combination immunotherapy regimen for CPI-failure patients that remain a large unmet medical need.
Methods
In the combination arm of the EVICTION Trial, patients with advanced, metastatic melanoma, bladder cancer, or NSCLC who failed ≥1 prior CPI were treated with ICT01 plus pembrolizumab (200 mg IV Q3W). i/RECIST was conducted every 8 weeks for efficacy (1° Disease Control Rate (DCR) and 2° Overall Response Rate (ORR)) in evaluable patients (recieved 3 cycles and had a Wk 8 i/RECIST). Blood samples were collected for ICT01 target occupancy, immunophenotyping and cytokine analysis (IFNg, TNFa, IL-1b/2/4/6/8/10/12/13). Tumor biopsies (baseline, Day 28) were used for IHC of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling.
Results
Overall, ICT01 + pembro was considered safe and well-tolerated across a range of ICT01 doses (700 mcg - 200 mg, n=36), without any DLTs. Activation & migration of all circulating γ9δ2 T cells was observed 30 min post dose that returned to baseline only at doses ≤7 mg. NK and CD8 T cell activation and margination was observed 24h post dose at doses of ICT01 ≥ 7 or ≥ 20 mg, respectively. 10- to 100-fold increases in IFNγ, TNFα and CXCL10 were observed for 24h post dose. Intra-tumoral γδ, CD3, CD3+Ki67+, CD8 and CD8+ Ki67+ cell densities increased as did gene signatures for intratumoral inflammation (ImmunoSign21, IFNγ response, T cell activation). Efficacy Evaluable (n=24): 6 Melanoma: 50% DCR, 33% ORR; 11 NSCLC: 36% DCR, 9% ORR; 6 Bladder: 33% DCR, 17% ORR. The 3 melanoma responders were IPI/Nivo refractory, with 2 PRs achieved at 2 & 20 mg in pts with high baseline γ9δ2 T cell counts.
Conclusions
ICT01 plus pembro is a novel immunotherapeutic approach worth further study in CPI failure pts.
Clinical trial identification
EudraCT 2019-003847-31; NCT04243499.
Legal entity responsible for the study
ImCheck Therapeutics.
Funding
ImCheck Therapeutics.
Disclosure
S. Champiat: Financial Interests, Personal, Advisory Board: Alderaan Biotechn, Avacta, Ellipses Pharma, Oncovita; Financial Interests, Personal, Invited Speaker: Amgen, Astellas, BMS, Eisai, Genmab, Janssen, Merck, Novartis, Roche, Seagen, UltraHuman8. M. Wermke: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca, Roche, Boehringer Ingelheim, Cellex, Lilly, MSD, Immatics, Pfizer. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. N. Vey: Financial Interests, Personal, Invited Speaker: Amgen, BMS, Janssen, Jazz Pharmaceuticals, Novartis, Roche. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Myers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana; Financial Interests, Personal, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Consultant: Sotio, SK Life; Financial Interests, Personal, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Institutional, Invited Speaker: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; External Advisory Board - Member: University of Arizona; External Scientific Advisory Board - Member: University of New Mexico; Scientific External Advisory Board - Member: University of California at San Diego. A. de Gassart: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. E. Valentin: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. P. Brune: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. M. Iche: Financial Interests, Personal and Institutional, Sponsor/Funding: ImCheck Therapeutics. C. Leparquier: Financial Interests, Personal, Sponsor/Funding: ImCheck Therapeutics. D. olive: Financial Interests, Personal, Stocks/Shares: ImCheck Therapeutics. A. Marabelle: Financial Interests, Personal, Advisory Board: Merck Serono, Amgen, Sotio, Pfizer, Seattle Genetics, Roche/Genentech, Merck, Centessa Pharmaceuticals, Shattuck Labs, Sanofi; Financial Interests, Personal, Invited Speaker: Novartis, Genmab. P.A. Frohna: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. All other authors have declared no conflicts of interest.
733MO - γδT cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects
- Joris Van De Haar (Amsterdam, Netherlands)
Abstract
Background
DNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB). Early evidence has indicated that MMR-d cancers that evade CD8+ T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation still respond to ICB, suggesting compensatory responsiveness of other immune effector cells in this context.
Methods
We performed genomic, (single-cell) transcriptomic and imaging-based analyses of ICB-naïve and ICB-treated MMR-d cancers, including those from TCGA and the DRUP and NICHE clinical trials, complemented by
Results
Paradoxically,
Conclusions
These data indicate that gd T cells are effectors of ICB therapy in patients with HLA class I-negative, MMR-d colon cancers. This underlines the potential of gd T cells in cancer immunotherapy, in particular for cancers with antigen presentation defects.
Clinical trial identification
NCT02925234.
Legal entity responsible for the study
Emile E. Voest.
Funding
N.F.C.C.d.M. is funded by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 852832). E.E.V. received funding from the Oncode Institute and Open Targets (Identification of targets modulating lymphocyte-mediated tumour cell killing [Project ID: OTAR2061]; Project Leaders M. Garnett and E.E. Voest) and the Josephine Nefkens Foundation.
Disclosure
All authors have declared no conflicts of interest.
734MO - Deep sequencing of the T-cell receptor reveals common and reproducible CD8 T-cell receptor signatures of response to checkpoint immunotherapy
- Benjamin P. Fairfax (Oxford, United Kingdom)
Abstract
Background
Immune checkpoint blockade (ICB) has revolutionized the treatment of metastatic melanoma (MM). However, robust biomarkers of response and the identity of key antigenic targets remains lacking. We have previously demonstrated the importance of large peripheral CD8+ T cell clones in the ICB response; these clones being more cytotoxic and especially sensitive to ICB. However, identifying key groups of T cells based on their T cell receptor (TCR) usage has remained elusive.
Methods
We performed deep sequencing of the TCR of CD8+ T cells isolated from peripheral blood of patients receiving ICB (n=96) for MM at multiple timepoints, along with control samples (n=43) and resected tumour specimens (n=10). Using the GLIPH2 algorithm, we grouped TCR into specificity groups, based on putative shared antigenic recognition, and explored associations with clinical outcome. We attempted to replicate findings in two independent cohorts.
Results
We identify TCR specificity groups that significantly increase in size from pre- to post-treatment in patients who have a clinical response to ICB. We call these ‘Emergent Responder Specificity Groups’ – ERSGs. We show that ERSGs are enriched for published known tumour-associated TCR and are more likely to be expanded intra-tumourally than non-ERSGs. Further, ERSGs are more likely to contain large T cell clones and have a greater cytotoxicity. Finally, the quantity of ERSGs present post-ICB correlated with clinical outcome in both replication cohorts.
Conclusions
This work identifies peripheral CD8+ TCR signatures that expand with immunotherapy and are associated with long-term clinical responses. These results demonstrate the prognostic utility of the peripheral immune repertoire and have potential widespread application in aiding in the identification of key antigens, with implications for T cell therapeutics.
Legal entity responsible for the study
The authors.
Funding
The Wellcome Trust.
Disclosure
M.R. Middleton: Financial Interests, Personal, Advisory Board, Advice on drug development and clinical trial design: Alkermes, Kineta, Silicon Therapeutics, Immunocore, Replimune; Financial Interests, Personal, Advisory Board, Advice on patient experience measures and research design: BMS; Financial Interests, Institutional, Invited Speaker, Fees for clinical trial conduct: Replimune; Financial Interests, Institutional, Invited Speaker, Fees for trial conduct: BMS, Alkermes, GSK, Merck KGa, MSD, Pfizer, Regeneron, Bioline, Novartis, Roche, Medivir; Financial Interests, Institutional, Funding, Educational grant towards IIS; fees for clinical trial conduct: Immunocore; Financial Interests, Institutional, Invited Speaker, Grant towards IIS: GRAIL; Non-Financial Interests, Multiple roles as reviewer and committee member: Cancer Research UK; Non-Financial Interests, Member: AACR, ASCO, ACP. B.P. Fairfax: Financial Interests, Personal, Conference Support: Bristol Myers Squibb. All other authors have declared no conflicts of interest.
Invited Discussant 732MO, 733MO and 734MO
- Sebastian Kobold (Munich, Germany)
735MO - Updated safety and efficacy from SURPASS, the phase I trial of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in previously treated patients with unresectable or metastatic tumors
- David S Hong (Houston, United States of America)
Abstract
Background
ADP-A2M4CD8 is a next-generation, specific peptide enhanced affinity receptor T-cell therapy modified with addition of a CD8α co-receptor to treat human leukocyte antigen A*02–eligible patients (pts) with unresectable or metastatic tumors positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4). ADP-A2M4CD8 has demonstrated promising anti-tumor activity with a favorable benefit to risk profile in the ongoing phase 1 SURPASS trial.1 Here we report updated clinical outcomes with additional pts treated.
Methods
The first-in-human trial consists of a modified 3+3 dose-escalation design with an expansion cohort. T-cells are obtained by leukapheresis, transduced with a lentiviral vector carrying the T-cell receptor and CD8α co-receptor genes, expanded in vitro, and infused back to the pt as ADP-A2M4CD8 following lymphodepleting chemotherapy. Safety, efficacy, pharmacokinetics, pharmacodynamics, and tumor biopsy characterization are evaluated.
Results
As of December 6, 2021, 29 pts (14 male, 15 female; all White) with a median age of 60 years (range: 31–75) received ADP-A2M4CD8 (1.02–9.95x109 transduced T-cells). Median MAGE-A4 expression H-score was 260 (range: 130–300). Overall response rate per RECIST v1.1 by investigator review for all cancer types was 31%; disease control rate was 75.9%. Adverse events were consistent with those typically associated with nonmyeloablative lymphodepletion, cellular therapy, and/or disease. This trial is ongoing; data from additional pts treated by August 2022 will be presented.
Conclusions
ADP-A2M4CD8 continues to show a favorable benefit to risk profile in multiple MAGE-A4+ unresectable or metastatic tumors. An additional treatment cohort has been included in the updated trial protocol to understand the potential benefits of ADP-A2M4CD8 combined with nivolumab. Emerging data signals encouraging clinical outcomes, especially for gastroesophageal and ovarian cancers for which two phase 2 trials have been or will be initiated. 1Hong DS, et al. E-poster 540P: ESMO 2021; Virtual.
Clinical trial identification
NCT04044859.
Editorial acknowledgement
This study was sponsored by Adaptimmune (Philadelphia, PA, USA). Writing and editorial support was from Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Adaptimmune.
Legal entity responsible for the study
Adaptimmune.
Funding
Adaptimmune.
Disclosure
D.S. Hong: Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Lilly, LOXO, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, TCR2, Teckro, Turning Point Therapeutics, Verstatem, VM Oncology; Financial Interests, Personal, Other, Travel accommodations, expenses: Bayer, Genmab, AACR, ASCO, SITC, Telperian; Financial Interests, Personal, Advisory Role: Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, Ziopharm; Financial Interests, Personal, Ownership Interest: Molecular Match, OncoResponse, Telperian. E. Calvo: Financial Interests, Personal, Full or part-time Employment: START, HM Hospitales Group; Financial Interests, Personal, Leadership Role: START; Financial Interests, Personal, Stocks/Shares: START, Oncoart Associated; Financial Interests, Personal, Honoraria: HM Hospitales Group; Financial Interests, Personal, Advisory Role: Nanobiotix, Janssen-Cilag, PsiOxus Therapeutics, Seattle Genetics, Roche/Genentech, Amcure, TargImmune Therapeutics, Servier, Bristol Myers Squibb, PharmaMar, Alkermes, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, BeiGene, Chugai Pharma, MonTa, MedSIR, MSD Oncology, Nouscom, Novartis, OncoDNA, Sanofi, Syneos Health, T-Knife, Boehringer Ingelheim; Financial Interests, Personal, Research Grant: BeiGene, START; Financial Interests, Institutional, Research Grant: Achilles; Financial Interests, Personal, President and Founder: Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences). J. Zugazagoitia: Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, Roche, Pfizer, Novartis, Guardant Health; Financial Interests, Personal, Invited Speaker: BMS, Pfizer, Roche, AstraZeneca, NanString, Guardant Health; Financial Interests, Personal, Travel Honoraria: BMS, Pfizer, Roche, AstraZeneca, NanoString; Financial Interests, Personal, Research Grant: BMS, AstraZeneca, Roche. J. Charlson: Financial Interests, Institutional, Advisory Board: Adaptimmune; Financial Interests, Institutional, Advisory Role: Deciphera. M.O. Butler: Financial Interests, Institutional, Research Grant: Merck, Takara Bio; Financial Interests, Personal, Advisory Role: Merck, BMS, Novartis, Immunocore, Adaptimmune, EMD Serono, GSK, Sanofi, Instil Bio, Iovance, Pfizer; Financial Interests, Personal, Invited Speaker: Merck, BMS, Novartis, Pfizer; Financial Interests, Personal, Safety Review Committee: Adaptimmune, GSK. V. Moreno Garcia: Financial Interests, Personal, Advisory Role: Roche, Bayer, BMS, Janssen, Basilea; Financial Interests, Institutional, Principal Investigator: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, Beigene, BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Sponsor, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith. A. Cervantes: Financial Interests, Institutional, Research Grant: Genentech, Merck Serono, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Adaptimmune, BeiGene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Takeda, FibroGen; Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Roche, Bayer, Servier, Pierre Fabre. B.A. Van Tine: Financial Interests, Personal, Advisory Role: Epizyme, CytRx, Janssen, Plexxicon, Bayer; Financial Interests, Personal, Consultant, Advisory Role/Speaker, Research/Trial Support, Travel Support: Lilly; Financial Interests, Personal, Speaker’s Bureau: Caris; Financial Interests, Personal, Research Grant, consulting/ad board: Pfizer; Financial Interests, Personal, Research Grant: Merck, Tracon; Financial Interests, Personal, Advisory Board: Immune Design, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Adaptimmune; Financial Interests, Institutional, Research Grant: Lilly, Merck; Financial Interests, Institutional, Trial Support: Oncothyreon, Gliknik, Celidex Therapeutics, ImClone Systems, Peregrine Pharmaceuticals, BIND Therapeutics, Regeneron Pharmaceuticals, MabVax Therapeutics, Millenium, AbbVie, Janssen Research Foundation, Jounce Therapeutics, EMD Serono, Puma Biotechnology, VentiRx Pharmaceuticals, Taiho Pharmaceuticals, Gilead Sciences, Incyte, Daiichi Pharmaceutical, Novartis, Pfizer, Acerta, Inventiv Health, Celgene, Sanofi, AstraZeneca, Merrimack Pharmaceuticals, Biothera Pharmaceuticals, Medimmune, Blueprint Medicines, Bristol Myers Squibb, Enzychem Lifesciences Corporation, Eisai, Genentech, Corvus, Johnson & Johnson, Threshold Pharmaceuticals, Bayer, BeiGene, GlaxoSmithKline, Molecular Insight Pharmaceuticals, Gem Pharmaceuticals, Deciphera Pharmaceuticals, Forma Therapeutics, Bavarian Nordic, Hoffmann-LaRoche, Caris Life Sciences, Morphotek, Soligenix, Eleison Pharmaceuticals, AADi, Immune Design, TRACON Pharmaceuticals, NanoCarrier, Advenchen Laboratories, Karyopharm Therapeutics, Hutchison MediPharma. M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Apexigen, Array BioPharma, AstraZeneca, Atreca, BeiGene, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Sanofi, Seven and Eight Biopharmaceuticals, Shattuck Labs, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, University of Michigan, WindMIL, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, Amgen; Financial Interests, Personal, Advisory Role, spouse: Astellas, Otsuka Pharmaceuticals; Financial Interests, Personal, Advisory Board: AbbVie, Achilles Therapeutics, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi; Financial Interests, Personal, Advisory Role: Association of Community Cancer Center; Financial Interests, Personal and Institutional, food/beverage/travel expenses: AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol Myers Squibb, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi. Q. Lin: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. T. Annareddy: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. F. Brophy: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. R. Broad: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. A. Derrac Soria: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. J. Navenot: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. J. Saro: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. E. Norry: Financial Interests, Personal, Full or part-time Employment: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. J.M. Clarke: Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb, Genentech, Spectrum, Adaptimmune, Medpacto, Bayer, AbbVie, Moderna, GlaxoSmithKline, Array, AstraZeneca, Grid Therapeutics, CBMG; Financial Interests, Personal, Invited Speaker: Merck, AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca, Merck, Pfizer, NGM Biopharmaceuticals, Spectrum, Genentech, Novartis, Turning Point, G1 Therapeutics, Vivacitas. All other authors have declared no conflicts of interest.
736MO - Personalized, off-the-shelf KRAS neoantigen-specific immunotherapy for the treatment of advanced solid tumors: Clinical benefit associated with decreases in ctDNA (SLATE-KRAS)
- Chrisann K. Kyi (New York, United States of America)
Abstract
Background
Targeting neoantigens derived from common driver mutations with a viral-based prime/boost vaccine can induce strong neoantigen-specific CD8 T cell responses and is a promising off-the-shelf immunotherapy.
Methods
A phase 1/2 study was conducted in patients (pts) with metastatic solid tumors harboring a specific vaccine-targeted neoepitope (HLA class I-restricted). The version 1 (V1) vaccine targeted 20 shared neoantigens from KRAS, TP53, b-catenin, and BRAF. An improved V2 vaccine only targeted KRAS neoantigens (G12C/D/V, Q61H). Pts receive an adenovirus prime followed by boosts with a self-amplifying mRNA with IV nivolumab 480 mg Q4W +/- SC ipilimumab 30 mg with vaccinations. Primary endpoints were safety (Phase 1) and response per RECIST v1.1 (Phase 2).
Results
26 pts with solid tumors were treated with V1. In pts with NSCLC (n=13, post-IO), 1 pt had an unconfirmed partial response (PR), 3 had stable disease (SD; one pt with -18% shrinkage completing 2 years of treatment), and 9 had progressive disease (PD). Molecular response was observed in 3 of 6 ctDNA-evaluable NSCLC pts (defined as > 50% decrease relative to baseline). Analysis of tumors showed increases in IFNg-related genes and vaccine-induced T cells. A V2 vaccine developed to target KRAS neoantigens more effectively induced greater levels of CD8 T cells than V1 in the first pts analyzed. 11 pts have been treated with V2 (NSCLC [n=4, post-IO] and MSS-CRC [n=7]). 1 NSCLC pt had an unconfirmed PR correlating with an 80% decrease in ctDNA. 2 pts with CRC had SD (one ongoing with >85% reduction in ctDNA, CA 19-9, and CEA and -14% shrinkage), and 5 pts with CRC had PD. 3 V2 pts progressed prior to the first boost vaccination at 4 weeks suggesting treating in earlier lines may provide time to generate robust neoantigen-specific CD8 T cells. The most common (>20%) treatment-related adverse events (TRAEs) were low grade, transient pyrexia, fatigue, nausea, injection-site reactions, vomitting, and chills and consistent across V1 and V2.
Conclusions
This off-the-shelf, neoantigen-specific vaccine demonstrated promising anti-tumor activity in pts with advanced solid tumors with tumor regression and/or molecular response.
Clinical trial identification
GO-005, NCT03953235, SLATE-KRAS.
Legal entity responsible for the study
Gritstone Bio, Inc.
Funding
Gritstone Bio, Inc.
Disclosure
C.K. Kyi: Financial Interests, Institutional, Principal Investigator: Merus, Gritstone bio, BMS. A. Spira: Financial Interests, Personal, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: Next Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Novartis, Boehringer Ingelheim, Astellas Pharma, MedImmune, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mersana, Mirati Therapeutics, Rubius, Synthekine, Blueprint Medicines. D.P. Carbone: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi-Sar, Eisai, EMD Serono/Merck, Flame Biosciences, Gritstone bio, GSK, Eli Lilly, Sanofi, Seattle Genetics. M.L. Johnson: Financial Interests, Personal, Advisory Board: Astellas, Otsuka; Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Amgen, Apexigen, Arcus, Array, AstraZeneca, Atreca, Beigene, Birdie, Boehringer Ingelheim, Checkpoint Therapeutics, Guardant Health, Genocea, Hengrui, Immunocore, Incyte, Janseen, Jounce, Gritstone bio, Lycera, Merck, Mirati, Oncomed, Regeneron, Ribon, Sanofi, Shattuck Labs, Stem CentRx, Syndax, Takeda, Tarveda, TCR2 Therapeutics, University of Michigan, WindMIL. B. Johnson: Financial Interests, Personal, Advisory Board: Gritstone bio, Inc., Incyte, Taiho Oncology; Financial Interests, Personal, Research Grant: BMS, Syntrix. H. Borghaei: Financial Interests, Personal, Advisory Board: BMS, Genentech, Eli-Lilly, Merck, EMD-serono, AstraZeneca, Novartis, Genmab, Regeneron, Amgen, Takeda, PharmaMar, Jazz Pharma, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTeo, Boehringer Ingelheim; Financial Interests, Personal, Training Discussion: Pfizer; Financial Interests, Personal, DSMB: Novartis; Financial Interests, Institutional, Clinical trial support: BMS, Amgen; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory role: Sonnetbio; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory board: Nucleai, Inspira (Rgenix); Financial Interests, Institutional, Invited Speaker, Investigator initiated trial support: BMS, Amgen, Lilly; Financial Interests, Personal and Institutional, Invited Speaker, Chair steering committee: Miratti; Financial Interests, Personal and Institutional, Invited Speaker: Amgen, AstraZeneca; DSMB: Novartis, Takeda, Incyte. A. Mahipal: Financial Interests, Personal, Advisory Board: Taiho, Incyte. J.R. Hecht: Financial Interests, Personal, Advisory Board: Ipsen, Merck, Acrotech Biopharma; Financial Interests, Institutional, Research Grant: ARMO Biosciences, Halozyme, Amgen, Merck, AbbVie, Advaxis, Astellas, Forty Seven, Immunomedics, Lilly, Gritstone bio, GSK, Arcus. D. Catenacci: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Bristol Myers Squibb, Five Prime Therapeutics , Genentech/Roche, Gritstone bio, Inc, Guardant Health , Lilly, Merck, Seattle Genetics, Taiho, Tempus; Financial Interests, Personal, Speaker’s Bureau: Foundation Medicine, Genentech/Roche, Guardant Health, Merck, Tempus. C. Liao: Financial Interests, Personal, Advisory Board: AstraZeneca, FirstThought LLC, Transthera, BluePrints Medicine, QED, Genentech, Cancer Experts Now, Histosonics, Ipsen, Exelixis; Financial Interests, Personal, Speaker Bureau: Eisai, Incyte; Financial Interests, Personal, Invited Speaker: OncLive; Financial Interests, Institutional, Invited Speaker, Research funding for investigator initiated trial: BMS. C. Presley: Financial Interests, Personal, Advisory Role: Onc Live, Potentia Metrics. J. Jaroslavsky: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.. D. Schenk: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.. K. Jooss: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.. A.R. Ferguson: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.. J.W. Goldman: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech, Eli Lilly, Janssen, AbbVie; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Genentech, Eli Lilly, Janssen, BMS, AbbVie. All other authors have declared no conflicts of interest.
737MO - EpCAM-targeted CAR-T cell therapy in patients with advanced colorectal and gastric cancers
- Weijia Fang (Hangzhou, China)
Abstract
Background
EpCAM is highly expressed in various cancer types of the digestive system and represent an interesting molecular therapeutic target. IMC001, an EpCAM targeted CAR-T cell therapy, showed promising anti-tumor activities in preclinical studies. Here we reported the initial dosage group in advanced GI cancers.
Methods
This first-in-human, open label, multi-centers trial involves a classic 3+3 design with separate EpCAM CAR-T cell dose escalations for monotherapy (Stage 1) and the combination with radiofrequency or microwave ablation (Stage 2) with dosage recommended by stage 1. EpCAM+ patients with relapsed or refractory digestive tumors who have no further standard treatment options and ECOG 0 or 1 are eligible to receive IMC001 at doses of 0.3, 1 or 3 million CAR-T cells/kg after lymphodepletion chemotherapy. The primary objective was to assess the safety, efficacy and cytokinetic profile of IMC001.
Results
As of 29 Apr 2022, a total of 7 patients with 4 colorectal cancers and 3 gastric cancers, received IMC001 infusion of 3×10ˆ5 cells/kg. 5 patients completed the 4 weeks of DLT follow-up visits. All patients experienced ≥G3 hematologic toxicity while no DLT was observed. The most common grade ≥3 AEs were decreases in lymphocyte, leukocyte and platelet count. One patient had a SAE of immune hepatitis occurred around 11 days after infusion of CAR-T cells and prolonged the hospitalization duration, resolved after symptomatic treatment. Grade 1 to 2 CRS were observed in 1 colorectal cancer patient and 1 gastric cancer patient. No ICANS was observed. Other adverse events related to the cell therapy were grade 1-2 of nausea, vomit, asthenia or pruritus and recovered quickly. CTC in the blood all decreased to 0 from 7 days to 4 weeks after infusion. Robust engraftment of CAR T cells and significant elevations of cytokines levels in all patients. Preliminary efficacy data showed that 4 out of 5 evaluable patients remain SD and 1 patient evaluated as PD at this lowest dosage.
Conclusions
This is the first CAR T product ever tested in human with the EpCAM target. IMC001 shows a favorable safety profile and reasonable anti-tumor activities at the initial dosage level in patients with refractory EpCAM+ cancers of digestive system. Updated data from open cohorts will be presented.
Clinical trial identification
NCT05028933, first posted: August 31, 2021. ChiCTR2100047129, first posted: June 8, 2021.
Legal entity responsible for the study
The First Affiliated Hospital of Zhejiang University, Shanghai Changhai Hospital.
Funding
Suzhou Immunofoco Biotech Co., Ltd.
Disclosure
W. Fang: Personal, Principal Investigator: The First Affiliated Hospital of Zhejiang University. T. Luo: Personal, Principal Investigator: The First Affiliated Hospital of Naval Medical University/Changhai Hospital of Shanghai. Z. Lu: Personal, sub-investigator: The First Affiliated Hospital of Naval Medical University/Changhai Hospital of Shanghai. H. Zhang: Personal, sub-investigator: The First Affiliated Hospital of Zhejiang University. C. Tong: Personal, sub-investigator: The First Affiliated Hospital of Zhejiang University. S. Wang: Financial Interests, Personal, Full or part-time Employment: Suzhou Immunofoco Biotechnology Co., Ltd. F. Tang: Financial Interests, Personal, Full or part-time Employment: Suzhou Immunofoco Biotechnology Co., Ltd. G. Ai: Financial Interests, Personal, Full or part-time Employment: Immunofoco Biotech.
Invited Discussant 735MO, 736MO and 737MO
- Alessandra Curioni (Zurich, Switzerland)