- Thomas B. Powles (London, United Kingdom)
LBA1 - BNT211: A Phase I/II trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6+ advanced solid tumors
- John B. Haanen (Amsterdam, Netherlands)
Abstract
Background
BNT211 comprises two drug products, a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen claudin 6 (CLDN6) and a CAR-T cell-Amplifying RNA Vaccine (CARVac). Preclinical studies demonstrated that CARVac mediates in vivo expansion of CAR-T cells, resulting in their improved persistence and functionality. Therefore, BNT211 aims to improve CAR-T therapy for solid tumors.
Methods
This first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with separate CLDN6 CAR-T cell dose escalations (single flat-dose) for monotherapy (Part 1) and the combination with CARVac (Part 2) based on 3 dose levels (DLs). In Part 2, CARVac is applied every 3 weeks starting at Day 4 post transplantation including a one-step intra-patient dose escalation. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0 or 1 are eligible for recruitment.
Results
As of 16th September 2021, 9 patients had been treated within three cohorts. DL1 of Parts 1 and 2 had been completed, while DL2 of Part 1 was ongoing. No dose-limiting toxicities and only a few adverse events related to the drug product and mainly linked to the lymphodepletion regimen have been reported. Pronounced cytopenia occurred in patients with testicular cancers who had recently received high dose chemotherapy and autologous stem cell transplantation. For these patients a lymphodepletion free cohort was recently opened. Manageable cytokine release syndrome (CRS, grade 1 to 2) without any signs of neurotoxicity has been observed in 1 patient of Part 2 DL1 and all patients of Part 1 DL2. Transient and moderate elevations of IL-6 serum levels occurred in remaining patients. Notably, administration of CARVac resulted in transient flu-like symptoms resolving within 24 h. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment in all patients. First preliminary efficacy data shows tumor shrinkage in 3 of 5 evaluable patients.
Conclusion
CLDN6 CAR-T cells ± CARVac show a favorable safety profile at doses tested and encouraging signs of clinical activity. Updated data from open cohorts will be presented.
Clinical trial identification
NCT04503278.
Disclosure
J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: BMS, Ipsen, Merck Serono, Molecular Partners, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Third Rock Ventures; Financial Interests, Institutional, Advisory Board: Achilles Tx, BioNTech US, Gadeta, Immunocore, Instil Bio, PokeAcel, T-Knife, Neogene Therapeutics; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Non-Financial Interests, Personal and Institutional, Member, Editor-in-Chief: ESMO IOTECH; Non-Financial Interests, Institutional, Funding, Grant support: Amgen, Asher Bio, BioNTech US, BMS, MSD, Novartis, Neogene Therapeutics. A. Mackensen: Financial Interests, Personal, Advisory Board: Miltenyi Biomedicine, Gilead/Kite, Novartis, BMS/Celgene, Ixaka; Financial Interests, Personal, Invited Speaker: Gilead/Kite, Novartis, BMS/Celgene. C. Koenecke: Financial Interests, Personal, Advisory Board: Janssen, Novartis, BMS/Celgene, Amgen, Sanofi, EUSAPharm, Gilead/Kite, Roche, GSK, Medigene. A. Desuki: Financial Interests, Personal, Advisory Board: Janssen, BMS, MSD, Eisei, Bayer; Financial Interests, Personal, Invited Speaker: BMS, Pfizer, Janssen. E. Wagner-Drouet: Financial Interests, Personal, Advisory Board: Novartis, Gilead/Kite, MSD. D. Heudobler: Financial Interests, Personal, Advisory Board: BMS, MSD, Janssen, Roche, Pfizer, Boehringer; Financial Interests, Institutional, Funding: BMS; Financial Interests, Personal, Speaker’s Bureau: BMS, Novartis. P. Borchmann: Other, Personal, Advisory Board: Roche, Amgen; Other, Personal, Invited Speaker: BMS, Celgene, AbbVie; Other, Personal and Institutional, Sponsor/Funding: Takeda Oncology, Novartis, MSD; Other, Personal and Institutional, Principal Investigator: Miltenyi Biotech; Other, Personal and Institutional, Advisory Board: Gilead. E. Wiegert: Financial Interests, Personal, Other, Consultant: BioNTech, Casi, Exicure, InflaRx, iTeos therapeutics, Molecular templates, Pieris, Roche, RS Oncology, Sapience, Vyriad Inc. C. Schulz: Financial Interests, Personal, Full or part-time Employment: BioNTech SE. B. Rengstl: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Royalties, Holds patents: BioNTech SE. L. Preußner: Financial Interests, Personal, Full or part-time Employment: BioNTech SE. Ö. Türeci: Financial Interests, Personal and Institutional, Member of the Board of Directors, CMO: BioNTech SE; Financial Interests, Personal and Institutional, Ownership Interest, Co-founder: BioNTech SE; Financial Interests, Personal, Stocks/Shares, Co-founder: BioNTech SE; Financial Interests, Personal, Royalties, Holds patents: BioNTech SE; Other, Personal and Institutional, Leadership Role, President: CIMT. U. Sahin: Financial Interests, Personal and Institutional, Member of the Board of Directors, CEO: BioNTech SE; Financial Interests, Personal and Institutional, Ownership Interest, Co-founder: BioNTech SE; Financial Interests, Personal, Stocks/Shares, Co-founder: BioNTech SE; Financial Interests, Personal, Royalties, Holds patents: BioNTech SE; Financial Interests, Institutional, Funding, Grant support from BMBF, DFG, EC: TRON; Financial Interests, Personal and Institutional, Leadership Role, Scientific advisor: TRON; Financial Interests, Personal, Royalties, Holds patents: TRON. All other authors have declared no conflicts of interest.
46MO - Promoting Functional Persistence in Solid Tumor CAR T-cell Therapy: Mesothelin-targeted CAR (M28z1XXPD1DNR) with T-cell Intrinsic PD1 Dominant Negative Receptor
- Prasad S. Adusumilli (New York, United States of America)
Abstract
Background
Following demonstration of the safety and efficacy signals of mesothelin-targeted chimeric antigen receptor (MSLN CAR) T cells (M28z) combined with PD-1 antibody (NCT02414269, Cancer Discovery 2021), herein, we investigate next-generation MSLN CAR, M28z1XXPD1DNR equipped with a modified CD3z (1XX), and a PD-1 dominant negative receptor (PD1DNR) that provides T-cell intrinsic checkpoint blockade.
Methods
MSLN CAR T cells (M28z, M28z1XX, M28zPD1DNR, or M28z1XXPD1DNR) were assessed in vitro following repeat antigen stimulation for cytotoxicity, proliferation, and cytokines secretion. Functional persistence was investigated in mice with orthotopic pleural mesothelioma following tumor rechallenges. Clinical safety and systemic persistence of M28z1XXPD1DNR CAR T cells was investigated in 4 pleural mesothelioma patients (NCT04577326).
Results
Following the first antigen stimulation, human T cells transduced with any of the four MSLN CARs exhibited similar cytotoxicity. However, following an antigen stress test with 6 antigen stimulations, M28zPD1DNR and M28z1XXPD1DNR CAR T cells demonstrated enhanced cytotoxicity (2-fold) and accumulation (3-fold) compared to M28z or M28z1XX CAR T cells. M28z1XXPD1DNR CAR T cells showed differential enrichment of cytokine production (1-5 -fold) involving cytokine signaling, effector immune responses, leukocyte activation, and differentiation. Intrapleural M28z1XXPD1DNR CAR T cells (1x105) eradicated mesothelioma (n=8) and prolonged survival. Functional persistence of CAR T cells is evident by resistance to tumor reestablishment following 14 rechallenges. In the clinical trial (NCT04577326), 4 patients (≥4 prior lines of therapy) received (12-20 months from diagnosis) either 1x106/kg (patients 1-3) or 3x106/kg (patient 4) intrapleural M28z1XXPD1DNR CAR T cells; no CAR T-cell related AEs of grade>2 were noted. CAR T-cell activation is evident by their detection in the peripheral blood for >30 days, associated with upregulated effector cytokines.
Conclusions
Supported by the preclinical functional persistence and the clinical safety and activation of M28z1XXPD1DNR CAR T cells to date, the phase I trial is ongoing.
Clinical trial identification
NCT04577326.
Legal entity responsible for the study
Memorial Sloan Kettering Cancer Center.
Funding
ATARA Biotherapeutics.
Disclosure
P.S. Adusumilli: Financial Interests, Personal, Funding: ATARA Biotherapeutics; Financial Interests, Personal, Advisory Board: ATARA Biotherapeutics; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BioArdis; Financial Interests, Personal, Advisory Board: Carisma Therapeutics; Financial Interests, Personal, Advisory Board: Imugene; Financial Interests, Personal, Advisory Board: ImmPACT Bio; Financial Interests, Personal, Advisory Board: Takeda Therapeutics; Financial Interests, Personal, Other, Dr. Adusumilli has patents, royalties, and intellectual property on mesothelin-targeted CARs and T-cell therapies, which has been licensed to ATARA Biotherapeutics, as well as method for detection of cancer cells using virus, and pending patent applications on T-cell therapies. ATARA Biotherapeutics; Financial Interests, Institutional, Other, Memorial Sloan Kettering Cancer Center (MSK) has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests: ATARA Biotherapeutics. S. Banerjee: Financial Interests: Amgen, Advisory Board, Personal; Clovis, Invited Speaker, Personal; Genmab, Advisory Board, Personal; Immunogen, Advisory Board, Personal; Mersana, Advisory Board, Personal; Merck Sereno, Advisory Board, Personal; MSD, Advisory Board, Personal; Pfizer, Invited Speaker, Personal; Roche, Advisory Board, Personal; Tesaro, Advisory Board, Personal; Tesaro, Invited Speaker, Personal; AstraZeneca, Advisory Board, Personal; AstraZeneca, Invited Speaker, Personal; GSK, Invited Speaker, Personal; GSK, Advisory Board, Personal; Takeda, Invited Speaker, Personal; Amgen, Invited Speaker, Personal; Oncxerna, Advisory Board, Personal; Medscape, Invited Speaker, Personal; Research to Practice, Invited Speaker, Personal; Peerview, Invited Speaker, Personal; PerciHealth, Stocks/Shares, Personal; AstraZeneca, Research Grant, Institutional; GSK, Research Grant, Institutional; Tesaro, Research Grant, Institutional. Non-Financial Interests: Verastem, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201; AstraZeneca, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored); Epsilogen, Advisory Role; ESGO, Other, Member of membership committee; Ovacome Charity, Advisory Role, Medical advisor to UK ovarian cancer charity; Lady Garden Foundation Charity, Other, Received research funding from UK based charity I have provided medical advice (non-remunerated). All other authors have declared no conflicts of interest.
47MO - Metabolic intervention during CAR T cell manufacturing improves persistence and antitumor efficacy
- Mathias Wenes (Lausanne, Switzerland)
Abstract
Background
Adoptive cell transfer (ACT) immunotherapy is showing impressive responses in hematological cancers and in metastatic melanoma. However, both the magnitude of tumor responses and the fraction of patients benefitting from this novel therapeutic approach remains limited. T lymphocytes prepared for ACT are generally terminally differentiated, resulting in inefficient engraftment. It has been shown that the infusion of T cells with a self-renewing, memory phenotype confers a stronger and more sustained anti-tumor response. Recently, it is becoming clear that T cell fate is tightly linked with specific metabolic characteristics. Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how pyruvate oxidation and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive.
Methods
We genetically and pharmacologically interfered with MPC activity in mouse and human T cells. Mechanistically, we performed metabolomics and epigenetic analyses. We translated our findings in a xenograft model for anti-CD19 chimeric antigen receptor (CAR) T cell treatment for human acute lymphoblastic leukemia (ALL).
Results
Genetic deletion of MPC drives CD8+ T cell differentiation towards a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production through glutamine and fatty acid oxidation, resulting in increased histone acetylation. The ensuing enhanced chromatin accessibility favored memory T cell differentiation, orchestrated by the transcription factor RUNX1. We used a small molecule MPC inhibitor to epigenetically imprint a memory phenotype during human CAR T cell manufacturing. Infusing unconditioned CAR T cells could not prevent mortality in mice with advanced ALL, while ACT with metabolically conditioned CAR T cells resulted in 100% complete responses. Similar results were obtained in a mouse melanoma model.
Conclusions
We show that metabolic intervention during CAR T cell manufacturing promotes memory T cell differentiation at the epigenetic level, allowing for a superior and long-lasting antitumor response in both hematological malignancies and solid tumors.
Legal entity responsible for the study
The authors.
Funding
Swiss Cancer League (KFS-4404-02-2018) and Roche pRED.
Disclosure
M. Wenes: Financial Interests, Personal and Institutional, Proprietary Information: University of Lausanne; Financial Interests, Institutional, Research Grant: Roche Glycart. D. Migliorini: Financial Interests, Institutional, Research Grant: Innosuisse. P. Ho: Non-Financial Interests, Personal, Advisory Board: Elixiron Immunotherapeutics; Financial Interests, Institutional, Funding: Elixiron Immunotherapeutics; Non-Financial Interests, Personal, Advisory Board: Acepodia; Non-Financial Interests, Personal, Advisory Board: Novartis. P. Romero: Financial Interests, Personal, Advisory Board: MaxiVax; Financial Interests, Institutional, Research Grant, University of Lausanne: Roche Glycart; Financial Interests, Personal and Institutional, Proprietary Information: University of Lausanne. All other authors have declared no conflicts of interest.
Invited Discussant abstracts LBA1, 46MO and 47MO
- Sebastian Kobold (Munich, Germany)
Q&A
- All Speakers (, Switzerland)
LBA4 - The Efficacy and Safety of TQ-B2450 alone/with Anlotinib in Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC): A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial
- Baohui Han (Shanghai, China)
Abstract
Background
TQ-B2450 is a novel humanized antibody, blocking programmed death-ligand 1. This study is to investigate the efficacy and safety of TQ-B2450 alone/with anlotinib, an oral multi-target tyrosine kinase inhibitor approved as ≥ 3 lines treatment in advanced NSCLC in China, in advanced/metastatic NSCLC patients (pts) without driver gene mutations.
Methods
This is a multicenter, randomized, double-blind, placebo-controlled study (NCT03910127). Eligible pts were ≥ 18 years old with ≥1 measurable lesion defined by RECIST v1.1, and had received at least first-line of standard chemotherapy but failed or intolerable, and were EGFR/ALK wild type IIIB-IV stage NSCLC. All pts were randomized in a 1:1:1 ratio to receive TQ-B2450 (1200mg IV on Day 1 Q21D) plus placebo, TQ-B2450 (1200mg IV on Day 1 Q21D) plus anlotinib (10 mg QD from day 1 to 14 of a 21-day cycle) or TQ-B2450 (1200mg IV on Day 1 Q21D) plus anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) until disease progression or treatment intolerance. The primary endpoint was PFS, secondary endpoints included safety, ORR, DCR and OS.
Results
Between July. 2019 and March. 2021, 33 and 68 pts in TQ-B2450 alone group and TQ-B2450 plus anlotinb group (average daily exposure dosage of anlotinb was 10.2 mg) were enrolled receptively. Baseline characteristics were generally balanced between groups. As of Oct 14, 2021, median follow up was 11.1 months. Median PFS was significantly longer in TQ-B2450 plus anlotinb group (6.9 months [95% CI 5.3-12.4]) than in TQ-B2450 alone group (2.7 months [95% CI 1.4-4.7]) (HR 0.43, 95% CI 0.25-0.73; P=0.0014). OS data were immature and not formly tested. ORR was significantly higher in TQ-B2450 plus anlotinb group than in TQ-B2450 alone group (30.9% vs. 3.0%, P=0.0043). Adverse events of ≥ grade 3 occurred in 67.7% of the pts in TQ-B2450 plus anlotinb group and in 21.2% of those in TQ-B2450 alone group.
Conclusion
A significantly and clinically meaningful improvement in PFS with TQ-B2450 plus anlotinib versus TQ-B2450 alone in all patients, supporting TQ-B2450 plus anlotinib as a promising treatment for advanced/metastatic NSCLC pts with prior systemic therapy.
Clinical trial identification
NCT03910127.
Disclosure
All authors have declared no conflicts of interest.
122MO - Nivolumab (NIVO) + ipilimumab (IPI) as first-line (1L) treatment (tx) for patients (pts) with advanced NSCLC (aNSCLC) and baseline (BL) brain metastases (mets): intracranial and systemic outcomes from Checkmate 227 Part 1
- Martin Reck (Grosshansdorf, Germany)
Abstract
Background
First-line NIVO + IPI has been shown to improve survival and systemic efficacy vs chemo in pts with aNSCLC with and without BL brain mets in a post hoc analysis from CheckMate 227 Part 1 (NCT02477826). Here we report intracranial and systemic efficacy, and safety data with a 4-y minimum follow-up.
Methods
Pts with untreated stage IV/recurrent NSCLC, no
Results
BL characteristics were generally similar between pts with (n = 134) and without (n = 1032) BL brain mets, and between tx arms, except for a greater proportion of pts with squamous histology and ECOG PS 0 in the no BL brain mets subgroup (both tx arms) and fewer pts with liver mets in the BL brain mets subgroup (NIVO + IPI). Efficacy data are shown in the table. NIVO + IPI prolonged OS vs chemo in pts with BL brain mets (HR 0.63, 95% CI 0.43–0.92). Median intracranial PFS was 8.6 vs 8.7 mo (HR 0.80, 95% CI 0.5–1.27); 4-y intracranial PFS rates were 28% vs 7%. In pts with BL brain mets, any-grade neurologic treatment-related adverse events occurred in 16% (NIVO + IPI) and 17% (chemo) of pts; all were grade 1/2.Table: 122MO
| With BL brain mets | Without BL brain mets | |||||
| Systemic | Intracranial | Systemic | ||||
| NIVO+IPI | Chemo | NIVO+IPI | Chemo | NIVO+IPI | Chemo | |
| Median OS, mo 95% CI | 17.4 9.2–28.5 | 13.7 10.5–16.2 | – | – | 17.1 15.3–20.0 | 13.9 11.8–15.3 |
| HR vs chemo 95% CI | 0.63 0.43–0.92 | – | 0.75 0.65–0.86 | |||
| 4-y OS rate, % | 28 | 8 | – | – | 27 | 16 |
| Median PFS,a mo | 5.4 | 5.8 | 8.6 | 8.7 | 4.9 | 5.4 |
| HR vs chemo | 0.77 | 0.80 | 0.80 | |||
| 4-y PFS rate, % | 15 | 2 | 28 | 7 | 13 | 3 |
| ORR, a n (%) | 22 (32) | 17 (26) | 20 (29) | 19 (29) | 173 (34) | 145 (28) |
| Median DOR, a mo | 24.9 | 8.4 | 45.5 | 32.0 | 20.7 | 5.8 |
| aPer BICR. | ||||||
Conclusions
At 4-y minimum follow-up, 1L NIVO + IPI showed durable survival benefit and a trend towards improved intracranial efficacy vs chemo in pts with aNSCLC and BL brain mets; no new safety signals were observed.
Clinical trial identification
NCT02477826.
Editorial acknowledgement
All authors contributed to and approved the presentation; writing and editorial assistance were provided by Ashvanti Valji, PhD, of Caudex, London, United Kingdom, funded by Bristol Myers Squibb.
Legal entity responsible for the study
Bristol Myers Squibb (Princeton, NJ).
Funding
Bristol Myers Squibb.
Disclosure
M. Reck: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Research Grant: Bristol Myers Squibb, Boehringer Ingelheim; Non-Financial Interests, Personal, Other, Travel / Accommodation / Expenses: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche. T. Ciuleanu: Financial Interests, Personal, Advisory Role: AstraZeneca, Amgen, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Roche, Sanofi, Servier, Pfizer; Non-Financial Interests, Personal, Other, Travel / Accommodations / Expenses: AstraZeneca, Amgen, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Roche, Sanofi, Servier, Pfizer. A. Pluzanski: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel / Accommodations / Expenses: Bristol Myers Squibb. R. Bernabe Caro: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, MSD, Takeda, Pfizer; Financial Interests, Personal and Institutional, Advisory Role: Roche; Financial Interests, Personal and Institutional, Research Grant: Roche. H. Linardou: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca. J. Burgers: Financial Interests, Personal and Institutional, Research Grant: MSD; Non-Financial Interests, Personal and Institutional, Advisory Board: Roche; Non-Financial Interests, Personal and Institutional, Funding: Roche. C. Gallardo: Financial Interests, Personal, Other, Consulting: MSD, AstraZeneca; Financial Interests, Personal, Other, Honoraria: MSD, AstraZeneca, Novartis, Roche; Financial Interests, Personal, Expert Testimony: AstraZeneca, Novartis; Non-Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Roche, MSD. M. Nishio: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical; Financial Interests, Personal, Research Grant: Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical; Financial Interests, Personal, Research Grant: Chugai Pharmaceutical; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Research Grant: Eli Lilly; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharmaceutical; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Advisory Board: Merck Biopharma; Financial Interests, Personal, Speaker’s Bureau: Merck Biopharma; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Advisory Board: Teijin Pharma; Financial Interests, Personal, Speaker’s Bureau: Teijin Pharma; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Speaker’s Bureau: AbbVie. S. Peters: Consultation / Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; Receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. L. Paz-Ares: Financial Interests, Personal, Leadership Role: Genomica, ALTUM sequencing; Non-Financial Interests, Personal, Speaker’s Bureau: MSD Oncology, Bristol Myers Squibb, Roche / Genentech, Pfizer, Lilly, Merck Serono; Financial Interests, Personal, Other, Travel / Accommodations / Expenses: Roche, AstraZeneca, MSD, Bristol Myers Squibb, Pfizer, Takeda; Financial Interests, Personal, Other, Honoraria: MSD Oncology, Bristol Myers Squibb, Roche / Genentech, Pfizer, Lilly, Merck Serono, AstraZeneca, Pharma Mar, Novartis, Celgene, Amgen, Sanofi, Ipsen, Servier, Bayer, Blueprint Medicines, Mirati Therapeutics, Takeda; Financial Interests, Personal, Research Grant: Bristol Myers Squibb, AstraZeneca, Pharma Mar, Kura Oncology, MSD. M. Hellmann: Financial Interests, Personal, Advisory Role: Merck, Bristol Myers Squibb, AstraZeneca, Genentech, Roche, Natera, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, Arcus, Adagene, Adicet, DaVolaterra, Eli Lilly, Genzyme/Sanofi, Janssen, Regeneron, Instil Bio, Mana Therapeutics, Pact Phar; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Shattuck Labs, Immunai, Arcus, Factorial; Financial Interests, Institutional, Licensing Fees, patent filed by MSKCC (PCT/US2015/062208) which has received licensing fees from PGDx: MSKCC. H. Borghaei: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Lilly, Celgene, Genentech, Pfizer, Boehringer Ingelheim, EMD Serono, Trovagene, Novartis, Merck, AstraZeneca, Genmab, Regeneron, Cantargia AB, BioNTech AG, AbbVie, Pharma Mar, Takeda, Amgen, HUYA Bioscience International, Sonnet, Rge; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Lilly, Celgene, Pfizer, Merck, Axiom Biotechnologies; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Lilly, Celgene, Merck, Millenium; Non-Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Bristol Myers Squibb, Lilly, Celgene, Genentech, Novartis, Merck, Clovis Oncology; Financial Interests, Personal, Stocks/Shares: Sonnet, Rgenix, Nuclaei; Financial Interests, Personal, Other, Data Safety Monitoring Board: Takeda, University of Pennsylvania, Incyte. S.S. Ramalingam: Financial Interests, Personal, Advisory Role: Amgen, Genentech/Roche, Lilly, Bristol Myers Squibb, AstraZeneca, Merck, Takeda, GlaxoSmithKline, Eisai, Daiichi Sankyo, Sanofi; Financial Interests, Personal, Research Grant: EMD Serono, Genmab, Advaxis, Tesaro, Bristol Myers Squibb, AstraZeneca, Merck, Takeda, GlaxoSmithKline. K. O’Byrne: Financial Interests, Personal, Advisory Role: Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Lilly Oncology, Novartis, Janssen, Teva, Takeda, Yuhan, Natera, Tristar; Financial Interests, Personal, Other, Honoraria: Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Lilly Oncology, Novartis, Janssen, Teva, Takeda, Yuhan, Natera, Tristar; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Lilly Oncology, Novartis, Janssen, Teva; Non-Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Lilly Oncology, Janssen; Non-Financial Interests, Personal, Speaker’s Bureau: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: RepLuca Pharmaceuticals, Carpe Vitae Pharmaceuticals, DGC Diagnostics; Non-Financial Interests, Personal, Member of the Board of Directors: Carpe Vitae Pharmaceuticals. N. Hu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. J. Bushong: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. L. Eccles: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. D. Grootendorst: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J.R. Brahmer: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, GlaxoSmithKline, Sanofi; Financial Interests, Personal, Other, Consulting: Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, GlaxoSmithKline, Sanofi, Regeneron; Financial Interests, Personal, Other, Honoraria: Genentech; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Non-Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Genentech; Financial Interests, Personal, Other, Data & Safety Monitoring Board Committee: GlaxoSmithKline, Sanofi. All other authors have declared no conflicts of interest.
Invited Discussant abstracts LBA4 and 122MO
- Francesco Facchinetti (Villejuif, France)
Q&A
- All Speakers (, Switzerland)
48MO - SQZ-PBMC-HPV-101: Preliminary results of a first-in-human, dose-escalation study of a cell-based vaccine in HLA A*02+ patients with recurrent, locally advanced, or metastatic HPV16+ solid tumors
- JONG CHUL PARK (Boston, United States of America)
Abstract
Background
Cancer vaccines aim to generate antigen-specific anti-tumor immune responses. However, their efficacy has been hampered by inefficient cross-presentation of the target antigens. Cell Squeeze® technology delivers target antigens directly into the PBMC’s cytosol via temporary cell membrane disruption through a microfluidic chip, which can achieve more efficient MHC-I antigen presentation compared to conventional cancer vaccines. SQZ-PBMC-HPV is an autologous cell vaccine targeting HPV16 viral oncoprotein E6 and E7 using the Cell Squeeze platform.
Methods
SQZ-PBMC-HPV-101 (NCT04084951) includes pts with advanced HPV16 cancers progressing after standard therapy who have ECOG 0-1, proper organ function, and RECIST measurable lesion(s). After leukapheresis, manufacturing of the cell product takes <24 hours with a vein-to-vein time of about 1 week. SQZ-PBMC-HPV was given IV q3w without a conditioning regimen. Double antigen priming (DP) was introduced in the last 2 cohorts. The response was assessed via RECIST 1.1. Paired biopsies were required at baseline and Day 28.
Results
18 pts [head and neck (9), anal (7), and cervical (2)] with median 3.5 prior lines of systemic cancer therapy were dosed in 4 dose-escalation cohorts (from 0.5 to 5.0 x10e6/kg [DP]). Treatment was well-tolerated and there were no DLTs, Grade (G) >2 related SAEs or related G >3 AEs. Paired biopsies of the tumor pre- and on-therapy indicated increased CD8 T cell activity across dose levels. Out of 5 response evaluable pts in the highest dose cohort, 1 unconfirmed partial response was observed in a pt with heavily pretreated PD-1 inhibitor refractory head and neck cancer. On-treatment biopsy of this pt showed significant increase in CD8 T cell infiltrates and PD-L1 expression.
Conclusions
In addition to demonstrating clinical feasibility of the Cell Squeeze® technology and favorable tolerability of engineered APCs, the data suggest that SQZ-PBMC-HPV cell-based vaccine can efficiently prime CD8 T cell responses to the target antigens leading to tumor shrinkage. Detailed efficacy, safety, and correlative biomarker data will be presented.
Clinical trial identification
NCT04084951.
Legal entity responsible for the study
SQZ Biotechnologies.
Funding
SQZ Biotechnologies.
Disclosure
J. Park: Non-Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies. J.C. Baranda: Non-Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies. M.M. Mita: Non-Financial Interests, Personal, Principal Investigator: SQZ Biotechnologies. W.T. Iams: Non-Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies. M.S. Gordon: Non-Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies. M. Taylor: Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies. N. Dhani: Non-Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies. S.M. Loughhead: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. R. Ji: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. R.F. Zwirtes: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. M. Kornacker: Financial Interests, Personal, Full or part-time Employment: Roche. O. Rosen: Financial Interests, Personal, Officer: SQZ Biotechnologies. H. Bernstein: Financial Interests, Personal, Officer: SQZ Biotechnologies. A. Jimeno: Non-Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies.
123MO - Monalizumab, cetuximab and durvalumab in first line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): a phase 2 trial.
- Dimitri A. Colevas (Stanford, United States of America)
Abstract
Background
Monalizumab is an immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), expressed on subsets of Natural Killer (NK) and tumor-infiltrating CD8+T cells. NKG2A blockade promotes anti-tumor immunity and may provide additional activity to cetuximab and durvalumab. We report here the safety and efficacy of monalizumab and cetuximab with the addition of durvalumab (cohort 3) in first-line treatment of patients with R/M SCCHN who had not received prior anti-PD-(L)1 mAb or chemotherapy in this setting.
Methods
This is a multicenter non-randomized multi-cohort phase 2 trial (NCT02643550) conducted in France and the US. Patients were enrolled regardless of PD-L1 status. Monalizumab (1500 mg Q4W), cetuximab (as per label) and durvalumab (1500 mg Q4W) were administered until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed per RECIST 1.1. Main secondary endpoints were safety, progression free survival (PFS) and overall survival (OS). Exploratory analyses were performed according to PD-L1 status.
Results
As of August 1, 2021, 40 patients were enrolled in cohort 3. Median age was 65 years (48-91), 12 (30%) patients had oropharynx HPV+ SCCHN and 25 (63%) had a current or prior smoking history. Median follow-up was 16.3 months (4.4-25.7); 13 patients had a confirmed response, ORR=32.5% [95%CI: 20-48], including 3 complete responses. Median time to response was 1.8 months [1.6-3.7], 6/13 responders were still on treatment, with median duration of response not yet reached [7.1-NR], median PFS was 6.9 months [4.4-9.3] and 12 months OS was 59% [45-77]. Results by CPS score will be presented. Grade 3-4 treatment-related adverse events (TRAE) occurred in 19 patients (48%); most frequent events were lipase or amylase increased and dermatitis acneiform (n=4, 4, and 3, respectively); 2 patients (5%) stopped all drugs due to TRAE.
Conclusions
Preliminary data suggest promising antitumor activity of the triplet of monalizumab, cetuximab and durvalumab in first line treatment of R/M SCCHN with an acceptable safety profile.
Clinical trial identification
NCT02643550.
Legal entity responsible for the study
Innate Pharma.
Funding
Innate Pharma and AstraZeneca.
Disclosure
D.A. Colevas: Financial Interests, Personal, Writing Engagements: IQVIA RDS, Inc; Financial Interests, Personal, Writing Engagements: ATARA Biotherapeutics. A.T. Pearson: Financial Interests, Personal, Advisory Board: Prelude therapeutics; Financial Interests, Personal, Advisory Board: New Rein LLC. J. Fayette: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Innate Pharma; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Other, Institutional, Research Grant: Seagens; Non-Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca. J.R. Bauman: Financial Interests, Personal, Advisory Board: AstraZeneca. D.R. Adkins: Financial Interests, Personal and Institutional, Principal Investigator: Innate Pharma; Financial Interests, Institutional, Research Grant: AstraZeneca. D.B. Marie, S.L. Cornen, P. André, F. Carrette, F. Rotolo, A. Boyer Chammard: Financial Interests, Personal, Full or part-time Employment: Innate Pharma. R.B. Cohen: Financial Interests, Personal, Advisory Board: Innate Pharma; Financial Interests, Personal, Advisory Board: AstraZeneca; Other, Personal and Institutional, Principal Investigator: AstraZeneca. All other authors have declared no conflicts of interest.
Invited Discussant abstracts 48MO and 123MO
- John B. Haanen (Amsterdam, Netherlands)
Q&A
- All Speakers (, Switzerland)