On November 12, 2020 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a pioneer in T-cell immunotherapy, leveraging its novel allogeneic EBV T-cell platform to develop transformative therapies for patients with serious diseases including solid tumors, hematologic cancers and autoimmune disease, reported the presentation of the first preclinical evaluation of ATA3271, a next-generation, off-the-shelf, allogeneic EBV CAR T-cell therapy targeting mesothelin designed for the treatment of solid tumors (Press release, Atara Biotherapeutics, NOV 12, 2020, View Source [SID1234570823]). These data are being featured in a poster presentation at the 35th Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (SITC 2020), November 11-14, 2020.
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"We have made meaningful progress advancing IND-enabling studies for ATA3271, an allogeneic mesothelin CAR T, which leverages our differentiated EBV T-cell platform and utilizes the PD1DNR and 1XX technologies to improve efficacy, persistence, and durability of response. Such innovative CAR T design addresses key hurdles for realizing the potential for CAR T therapies in solid tumor settings," said Jakob Dupont, Global Head of Research and Development at Atara. "Mesothelin, an antigen associated with aggressive solid tumors, is a promising target for tumor-specific therapy and combined with our EBV T-cell platform and the PD1DNR and 1XX technologies has led to the potent preclinical antitumor activity of ATA3271 that functionally persists after multiple tumor cell challenges."
Results presented at SITC (Free SITC Whitepaper) detail findings from in vitro and in vivo evaluation of ATA3271. Specifically, in vitro functional studies show potent antitumor activity of ATA3271 against mesothelin-expressing cell lines, with potency maintained in the presence of high tumor PD-L1 expression. These data support the design of ATA3271, which expresses a dominant negative version of PD-1 receptor, to maintain function in the presence of suppressive checkpoint ligands commonly associated with solid tumor microenvironments. In addition, results further support the combined functional design of ATA3271’s 1XX costimulatory domain technology in maintaining memory phenotype while limiting cell exhaustion in the context of repeated tumor cell challenges.
Furthermore, ATA3271 retains reduced allocytotoxic function against HLA mismatched targets, a characteristic that is associated with Atara’s allogeneic EBV T-cell platform that leverages enrichment of endogenous EBV-TCR function to decrease clinical risks for GvHD. We also believe that our allogeneic EBV CAR T-cell platform may prevent cellular exhaustion and augment in vivo expansion.
In vivo, ATA3271 exhibited potent antitumor activity and significant survival benefit in mice implanted with MGM-PDL1 cells that highly express both mesothelin as well as PD-L1. This in vivo potency was demonstrated without evident toxicities. All mice treated with ATA3271 (n=10) survived through the study duration, while control mice (n=10) all died within a median duration of 25 days (15- to 35-day survival range), post tumor implantation. Evidence in six of ten mice also showed that ATA3271 persisted in vivo by day 51. Ex vivo analysis of a subset of these persistent cell populations (n=4) demonstrated maintenance of phenotypic memory markers over the duration of the in vivo activity.
Mesothelin is a tumor-specific antigen that is commonly expressed at high levels on the cell surface in many aggressive solid tumors including mesothelioma, triple-negative breast cancer, esophageal cancer, ovarian cancer, pancreatic cancer and non-small cell lung cancer and is an attractive target for immune-based therapies. Both in vitro and in vivo results for ATA3271 suggest that allogeneic mesothelin-CAR-engineered EBV T cells are a promising approach for the treatment of mesothelin-positive cancers.
"The results presented today further support the continued development of our allogeneic mesothelin-targeted next-generation CAR T program," said AJ Joshi, M.D., Senior Vice President and Chief Medical Officer at Atara. "We look forward to building upon these foundational preclinical studies to advance ATA3271 in the clinic with the goal of bringing a potentially transformative therapeutic option to treat aggressive solid tumors including mesothelioma."
Atara’s next generation CAR T immunotherapy franchise for mesothelin also includes autologous ATA2271. The U.S. Food and Drug Administration (FDA) recently accepted an Investigational New Drug (IND) application to initiate a Phase 1 clinical study of ATA2271 for the treatment of advanced mesothelioma.