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.
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).
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.
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.
NCT04577326.
Memorial Sloan Kettering Cancer Center.
ATARA Biotherapeutics.
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.