On January 3, 2019 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported that it has exclusively licensed worldwide rights to a mesothelin-targeted chimeric antigen receptor T-cell (CAR T) immunotherapy for solid tumors from Memorial Sloan Kettering Cancer Center (MSK) (Press release, Atara Biotherapeutics, JAN 3, 2019, View Source [SID1234532388]). The most advanced program in Atara’s CAR T collaboration with MSK will focus on development of a next-generation, mesothelin-targeted CAR T using novel 1XX CAR signaling domain and PD-1 dominant negative receptor (DNR) checkpoint inhibition technologies for patients with mesothelin-associated solid tumors.
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"We are excited by the promising initial clinical results of the mesothelin-directed CAR T approach and believe mesothelin, an antigen well recognized as associated with aggressive solid tumors, is a promising target for developing a next-generation CAR T incorporating our PD-1 DNR technology," said Prasad S. Adusumilli, M.D., FACS, Deputy Chief of Thoracic Service, Director of Mesothelioma Program and Head of Solid Tumors Cell Therapy at the Cellular Therapeutics Center at MSK.
PD-1 DNRs are modified PD-1 receptors that lack inhibitory function and are designed to enhance CAR T efficacy in solid tumors without the need for development of a CAR T in combination with a PD-1 checkpoint inhibitor. Animal models have demonstrated that CAR T immunotherapies with a PD-1 DNR result in enhanced activity against solid tumors1.
"We look forward to collaborating with Atara to develop a next-generation mesothelin-targeted CAR T immunotherapy," said Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, and Head, Gene Expression and Gene Transfer Laboratory at MSK. "Our novel mesothelin 1XX CAR is designed to extend functional CAR T cell persistence by sustaining T cell effector functions without precipitating exhaustion, provides a complementary technology to tackle challenging tumor microenvironments."
Mesothelin is a solid tumor-associated antigen that is expressed at high levels on the surface of cells in aggressive solid tumors including mesothelioma, triple-negative breast cancer, esophageal cancer, pancreatic cancer and non-small cell lung cancer. Initial results from an ongoing MSK investigator-sponsored Phase 1 study (NCT02414269) of a mesothelin-targeted CAR T immunotherapy for patients with malignant pleural cancers were presented at the 2018 American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting and support activity and safety in patients with advanced mesothelioma2,3. This ongoing Phase 1 dose-escalation study continues to accrue patients and enhanced response rates were observed when patients were subsequently treated with pembrolizumab, a PD‑1 checkpoint inhibitor. MSK is also investigating mesothelin-targeted CAR T cells for patients with advanced breast and lung cancer (NCT02792114). Additional results from these ongoing studies are expected to be presented at upcoming scientific congresses.
"Our CAR T strategy includes collaboration with investigators on cutting-edge technologies to advance programs with near-term clinical potential," said Dietmar Berger, M.D., Ph.D., Global Head of Research and Development of Atara Biotherapeutics. "Based on the encouraging MSK Phase 1 clinical experience, we are progressing a next‑generation, mesothelin‑targeted CAR T that leverages MSK technologies designed to further enhance responses in patients with mesothelioma and other advanced solid tumors. We are also developing three additional next-generation and off-the-shelf, allogeneic CAR T immunotherapies in oncology for patients with acute myelogenous leukemia (AML) and B-cell malignancies, leveraging Atara’s world-class T cell manufacturing capabilities and research expertise."
In the MSK investigator-sponsored Phase 1 study presented at the 2018 ASGCT (Free ASGCT Whitepaper) Annual Meeting, patients with malignant pleural cancers were administered a mesothelin-targeted autologous CAR T immunotherapy regionally into the chest cavity following cyclophosphamide pre-conditioning (NCT02414269). Of the six patients treated with CAR T cells following preconditioning cyclophosphamide who subsequently received checkpoint inhibitors, one showed a complete metabolic response (CMR), two had a partial response (PR) and one exhibited stable disease (SD). Mesothelin-targeted CAR T immunotherapy and PD-1 checkpoint inhibition was well-tolerated with no adverse events greater than Grade 2 and no on-target, off-tumor toxicity.
Financial terms of the agreement were not disclosed.
References
1Cherkassky L, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016 Aug 1;126(8):3130-44. doi: 10.1172/JCI83092. Epub 2016 Jul 25.
2Adusumilli PS, et al. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CART cells: safety and efficacy – a preliminary report. Abstract 342; 2018 ASGCT (Free ASGCT Whitepaper) Annual Meeting; Chicago, IL; May 16-19, 2018.
3Adusumilli PS, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014 Nov 5;6(261):261ra151. doi: 10.1126/scitranslmed.3010162.