On May 15, 2020 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a pioneer in T-cell immunotherapy leveraging its novel allogeneic EBV T-cell platform to develop treatments for patients with severe diseases including solid tumors, hematologic cancers and autoimmune disease, reported that an abstract describing the preclinical safety, improved functional characteristics and antitumor efficacy of ATA2271, a next-generation autologous chimeric antigen receptor (CAR) T cell therapy targeting mesothelin, was selected for a late-breaking poster presentation at the second American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting 2020 to be held on June 22-24, 2020 (Press release, Atara Biotherapeutics, MAY 15, 2020, View Source [SID1234558167]).
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Although CAR T cell therapies have been approved for certain hematologic malignancies, new approaches are needed in solid tumor settings. Mesothelin is a tumor-specific antigen that is commonly expressed at high levels on the cell surface in many aggressive solid tumors including mesothelioma. Atara has selected mesothelin as the target for both the ATA2271 autologous and the ATA 3271 allogeneic programs along with novel CAR T-cell technologies to further enhance activity.
Data being presented for the first time at AACR (Free AACR Whitepaper) detail results from IND-enabling preclinical studies with ATA2271 technologies, designed to help overcome current CAR T challenges with targeting solid tumors, including the novel 1XX CAR signaling domain and a dominant-negative programmed death-1 receptor (PD1DNR). These studies, led by Prasad Adusumilli, MD and collaborators at Memorial Sloan Kettering Cancer Center (MSK) provide both in vitro and in vivo evidence of the preclinical safety, improved functional characteristics and enhanced anti-tumor efficacy of ATA2271.
"These data support the combined addition of novel design elements in this next-gen CAR T therapy, including both 1XX co-stimulatory signaling and PD1DNR, that were associated with less cell exhaustion, improvements in functional persistence, serial cell killing, and in vivo efficacy which was maintained through multiple tumor re-challenges," said Blake T. Aftab, Ph.D., Vice President of Preclinical and Translational Science for Atara Biotherapeutics. "These results are consistent with the larger body of data supporting key CAR T characteristics that are preferred when targeting mesothelioma and potentially a range of solid tumors."
Specifically, in vitro, ATA2271 exhibited antigen-specific cytotoxicity, accumulation and effector cytokine secretion, while in vivo results demonstrated that a single dose of ATA2271 led to tumor eradication and superior survival in mice compared to mesothelin-targeted M28z CAR T cells. Mice treated with a single dose of ATA2271 also showed sustained and persistent protection from tumor reestablishment upon 10 additional tumor re-challenges. Results from the study demonstrated the proposed advantages associated with functional persistence and cell-intrinsic PD-1 checkpoint blockade.
"We look forward to advancing our next-generation CAR T program which includes ATA2271 and off-the-shelf, allogeneic MSLN-directed CAR T immunotherapy, ATA3271, and expanding the investigation of our technology in other mesothelin-expressing solid tumors," said AJ Joshi, MD, Senior Vice President and Chief Medical Officer of Atara Biotherapeutics.
These data will be used to support submission of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) in the second or third quarter of 2020 followed by the initiation of a Phase 1 clinical trial in patients with advanced mesothelioma.
About ATA2271
In collaboration with MSK, Atara is developing ATA2271, a next-generation autologous mesothelin-targeted CAR T using novel 1XX CAR signaling and programmed death-1 (PD-1) dominant negative receptor (PD1DNR) checkpoint inhibition technologies (M28z1XX PD1DNR CAR T cells). This technology is supported by the safety and anti-tumor efficacy that was exhibited in prior studies evaluating a mesothelin-directed CAR utilizing a CD28 co-stimulatory signally domain. This regionally delivered autologous mesothelin-targeted construct (using M28z CAR T cells) combined with PD-1 antibody is being studied in two ongoing MSK Phase 1 trials in patients with malignant pleural disease and mesothelioma, non-small cell lung cancer, and breast cancer (NCT02414269 and NCT02792114).
Details of the poster presentation and abstract are as follows:
Abstract #: LB-378
Title: "Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial"
Presentation Date and Time: Available starting on June 22nd
Session Title: Late-Breaking Research: Immunology 2
Category and Subclass: Immunology
Authors: Stefan Kiesgen, Camille Linot, Hue T. Quach, Jasmeen Saini, Rebecca Bellis, Srijita Banerjee, Zhaohua Hou, Navin K. Chintala, Michel Sadelain, Prasad S. Adusumilli
Affiliations: Memorial Sloan Kettering, New York, NY
Dr. O’Reilly, Dr. Sadelain, and Dr. Adusumilli have intellectual property interests in technologies licensed by Memorial Sloan Kettering (MSK) to Atara. Related to ATA2271 and ATA3271, Dr. Sadelain and Dr. Adusumilli have intellectual property interests in technology licensed by Memorial Sloan Kettering (MSK) to Atara. Dr. O’Reilly and Dr. Adusumilli also have compensated consulting relationships with Atara. MSK has institutional financial interests related to Atara in the form of intellectual property rights and associated interests by virtue of licensing agreements between MSK and Atara.