ATA2271 / Memorial Sloan-Kettering Cancer Center - LARVOL DELTA

A phase I trial of intraperitoneal (IP) mesothelin (MSLN)-targeted CAR T-cell therapy in patients with MSLN-positive esophagogastric cancer (EGC) with peritoneal carcinomatosis. (ASCO-GI 2025) - "M28z1XXPD1DNR CAR T-cells are a next-generation MSLN-targeted CAR, equipped with a modified CD3z (1XX), and a PD-1 dominant negative receptor (PD1DNR) that provides T-cell intrinsic checkpoint blockade...Lymphodepletion with fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day is given for 3 days prior to the CAR T cell infusion...The trial is currently enrolling patients. Dose-escalation scheme based on the continuous reassessment method."

CAR T-Cell Therapy • Clinical • IO biomarker • P1 data • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSLN

A Study of Mesothelin-Targeted CAR T-Cell Therapy in People With Esophagogastric Cancer (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center

New P1 trial • Breast Cancer • Diabetes • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Metabolic Disorders • Oncology • Peritoneal Cancer • Solid Tumor

Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting | N=30 ➔ 14

CAR T-Cell Therapy • Checkpoint inhibition • Enrollment change • Enrollment closed • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2024 ➔ Sep 2025

CAR T-Cell Therapy • Checkpoint inhibition • Trial completion date • Trial primary completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Tumor-targeted non-ablative radiation promotes solid tumor CAR T-cell therapy efficacy. (PubMed, Cancer Immunol Res) - "We use a non-ablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, anti-tumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor...Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich" cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells."

CAR T-Cell Therapy • IO biomarker • Journal • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • MSLN

KTE-X19, AN ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY, IN ADULT PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA: END OF PHASE 1 RESULTS OF ZUMA-3 (EHA 2019) - P1/2; "Background KTE-X19 is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy under investigation for adult relapsed/refractory acute lymphoblastic leukemia. Conclusion KTE-X19 dosing and safety management have been successfully refined by testing 3 cell doses and evaluating a new AE management guideline with altered corticosteroids/tocilizumab use for NEs/CRS. The pivotal Phase 2 portion of ZUMA-3 is ongoing at the 1 × 106 dose with revised AE management."

CAR T-Cell Therapy • Clinical • P1 data

An Individualized Risk Mitigation Approach for Safety: Experience from the Mosunetuzumab (CD20/CD3 Bispecific Antibody) Development Program in Relation to Neurotoxicity Risk (ASH 2019) - P1; "Introduction: Neurologic toxicities have resulted in restrictions in driving/engaging in hazardous occupations and activities for pts receiving marketed T-cell-engaging CD19-directed bispecific antibodies and chimeric antigen receptor T-cell (CAR-T) therapies. Based on these analyses, the driving restriction that applied to all pts for the duration of M treatment was amended to a restriction covering the first 2 cycles only in a subset of pts who had aNHL and elevated CRP at baseline. This novel approach of individualized risk mitigation for driving based on in-depth assessment of NAEs allows for a more targeted and patient-centric mitigation strategy to optimize the protection of pts at risk, and is useful during clinical development when the safety profile is being characterized. As further data are accumulated, the multivariate analysis can be updated to further refine the pts at risk for DI-CC-NAE."

Clinical • CRP

Hematological Count Recovery in Patients Undergoing Treatment with Chimeric Antigen Receptor T Cells (CAR T) (ASH 2019) - P1; "Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months post-CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients. The association of count recovery and CAR construct can be influenced by underlying diagnosis as specific CAR constructs were used for specific diagnosis. Since patients with no disease response were excluded and were censored at progression, these effects are less likely to be affected by disease response; however the association of depth of response could not be evaluated in this study."

CAR T-Cell Therapy • Clinical

MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy (ASH 2019) - P1; "Background: CD19-targeted chimeric antigen receptor T cell (CAR T) therapies have remarkable overall response rates (ORR) for relapsed diffuse large B cell lymphoma (DLBCL)...Several CAR products were used, including axicabtagene ciloleucel (n=8), JCAR017 (n=3, per NCT02631044), tisagenlecleucel (n=1) and EGFRt/19-28z/4-1BBL “armored” CAR (n=1, per NCT03085173)...All had cyclophosphamide and fludarabine lymphodepletion... Use of RT as a CAR T bridging strategy is feasible and associated with excellent pre-CAR local control and initial post CAR ORR in a cohort of heavily pre-treated DLBCL patients. We observed moderate serious CAR toxicity that did not appear to be augmented by RT. Future efforts should clarify the optimal RT timing/dose and assess the potential for incremental immunogenicity with combined therapy."

Impact and Safety of Chimeric Antigen Receptor T Cell Therapy in Vulnerable Older Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (ASH 2019) - "We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system."

CAR T-Cell Therapy • Clinical

Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Recruiting | Trial completion date: Sep 2023 ➔ Sep 2024 | Trial primary completion date: Sep 2023 ➔ Sep 2024

CAR T-Cell Therapy • Checkpoint inhibition • Enrollment open • Trial completion date • Trial primary completion date • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Atara Biotherapeutics Announces Third Quarter 2022 Financial Results and Operational Progress (Businesswire) - "ATA2271 (Solid Tumors Over-Expressing Mesothelin): The ongoing Phase 1, Memorial Sloan Kettering Cancer Center (MSK)-conducted, and investigator led clinical study of autologous mesothelin chimeric antigen receptor (CAR) T-cell therapy, ATA2271, has resumed after a voluntary pause in enrollment earlier this year. Details on the latest findings, including clinical and safety observations, will be presented at a session titled, 'Building on CAR-T Experience in Mesothelioma,' at ESMO Immuno-Oncology on December 7, 2022."

P1 data • Trial status • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • Thoracic Cancer

Promoting Functional Persistence in Solid Tumor CAR T-cell Therapy: Mesothelin-targeted CAR (M28z1XXPD1DNR) with T-cell Intrinsic PD1 Dominant Negative Receptor (ESMO-IO 2021) - P1, P1/2 | "Clinical safety and systemic persistence of M28z1XXPD1DNR CAR T cells was investigated in 4 pleural mesothelioma patients (NCT04577326)...Legal entity responsible for the study Memorial Sloan Kettering Cancer Center. Funding ATARA Biotherapeutics."

CAR T-Cell Therapy • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma (clinicaltrials.gov) - P1 | N=7 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting | N=30 ➔ 7

CAR T-Cell Therapy • Checkpoint inhibition • Enrollment change • Enrollment closed • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Atara Biotherapeutics Provides Update on Strategic Collaboration with Bayer (Businesswire) - "Atara Biotherapeutics...announced that it received notification of Bayer’s intention to end the exclusive worldwide licensing agreement for next-generation mesothelin-directed CAR T-cell therapies. The collaboration included the funding and development of ATA3271, an armored allogeneic T-cell immunotherapy, and an autologous version, ATA2271, for high mesothelin-expressing tumors such as malignant pleural mesothelioma and non-small-cell lung cancer....Upon termination of the agreement in September 2022, the rights and licenses granted by Atara to Bayer under the collaboration will be returned to Atara....'We will postpone the anticipated IND filing for ATA3271 beyond the fourth quarter of 2022'."

IND • Licensing / partnership • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Atara Biotherapeutics Announces First Quarter 2022 Financial Results and Operational Progress (Businesswire) - "Atara and MSK expect to provide a Phase 1 data update for ATA2271 in H2 2022. IND-enabling work for ATA3271, our off-the-shelf, allogeneic CAR-T therapy targeting mesothelin using next-generation PD-1 DNR and 1XX CAR technologies for patients with advanced mesothelioma, is advancing, with the IND filing anticipated in Q4 2022....Atara continues to progress ATA3219, a potential best-in-class, allogeneic CAR T for B cell malignancies expressing CD19. Atara is on track to submit an IND in Q4 2022."

IND • P1 data • Hematological Malignancies • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

Atara Biotherapeutics Provides Update on ATA2271 Autologous CAR T Trial (Businesswire) - P1 | N=30 | NCT04577326 | "Atara Biotherapeutics, Inc...reported Memorial Sloan Kettering Cancer Center’s (MSK) notification to the U.S. Food and Drug Administration (FDA) of a fatal serious adverse event (SAE) associated with a patient treated in the ongoing Phase 1, MSK-conducted dose-escalation clinical study of autologous mesothelin CAR T, ATA2271. MSK has voluntarily paused enrollment of new patients in the study on a temporary basis while additional information regarding the case is gathered and reviewed. The FDA has notified MSK of its agreement with this approach...The median survival of treated patients with malignant pleural mesothelioma is 9-17 months even with successful completion of a combination of chemotherapy, aggressive surgical resection, and radiation therapy....Within these two cohorts, no dose limiting toxicities have been reported to date."

FDA event • P1 data • Trial status • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Atara Biotherapeutics Announces Preliminary Results for ATA2271, a Next-Generation Autologous Mesothelin-targeted CAR T-cell Therapy for Solid Tumors, at ESMO Immuno-Oncology Congress 2021 (Businesswire) - P1, N=30; NCT04577326; "In the ongoing Phase 1 dose finding study (NCT04577326), intrapleural administration of ATA2271 was found to be well-tolerated at lowest dose levels with no CAR T-cell related adverse events (AEs) of Grade >2 observed and no AEs of Grade >3 to date in the study. All four patients had received at least four prior lines of therapy. Importantly, ATA2271 CAR T-cells persisted in patients’ peripheral blood for greater than four weeks and was associated with upregulated effector cytokines."

P1 data • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

Atara Biotherapeutics Announces Preliminary Results for ATA2271, a Next-Generation Autologous Mesothelin-targeted CAR T-cell Therapy for Solid Tumors, at ESMO Immuno-Oncology Congress 2021 (Businesswire) - "Specifically, in vitro functional studies show potent antitumor activity of ATA2271 following repeat antigen stimulation, with enhanced expansion observed in cells equipped with a PD-1 dominant negative receptor (PD1DNR) that provides T-cell intrinsic checkpoint blockade compared to CAR T-cells with a modified CD3z (1XX) alone."

Preclinical • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Atara Biotherapeutics Announces Third Quarter 2021 Financial Results and Operational Progress (Businesswire) - "The first presentation of preclinical, clinical, and translational data from the lowest dose cohorts of the open-label, single-arm Phase 1 clinical study of ATA2271, an autologous CAR-T therapy targeting mesothelin, designed to improve efficacy, persistence, and durability of response for patients with advanced mesothelioma, will take place during a Mini Oral session at the ESMO Immuno-Oncology Congress on December 9, 2021 (presentation #46MO. Preclinical data for ATA3271 will be presented at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting, taking place November 10-14, 2021 (poster #136)."

Preclinical • Oncology

Easix and Modified-Easix Are Early Predictors of Severe Cytokine Release Syndrome and Neurotoxicity in Patients Treated with Chimeric Antigen Receptor T Cells (ASH 2019) - P1; "Methods We analyzed 2 different populations of adult CAR T cells pts treated at our institution: 1) B-cell acute lymphoblastic leukemia (B-ALL) pts treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) aggressive diffuse large B-cell lymphoma (DLBCL) pts treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval starting from 2018. Moreover, both high EASIX and mEASIX scores on day +1 and day +3 are associated with occurrence of grade ≥3 CRS and grade ≥3 ICANS, respectively. We conclude that EASIX and mEASIX, as markers of endothelial damage and inflammation, could be useful as early predictors in guiding treatment decisions before the onset of severe symptoms."

CAR T-Cell Therapy • Clinical • Acute Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Hemophilia • Immunology • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • IL6

AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study (ASH 2019) - P1; "Inhibitors of DHODH are currently in clinical use for the treatment of rheumatoid arthritis (leflunomide) and multiple sclerosis (teriflunomide)...There are no limits on the number of prior lines of therapy and patients may have received prior stem cell transplant or chimeric antigen receptor T-cell therapy...Further expansion may be undertaken if AG-636 shows high activity in specific subtypes of lymphoma, either in the clinic or in preclinical models. The experience in this study with the pharmacokinetics, pharmacodynamics, and safety of AG-636 will inform the optimal starting dose and regimen for evaluation in subsequent studies."

Clinical • New P1 trial • P1 data • CNS Disorders • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Immunology • Leukemia • Lymphoma • Multiple Sclerosis • Oncology • Rheumatoid Arthritis • Rheumatology

Preliminary Safety, Pharmacokinetic, and Pharmacodynamic Results from a Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Noncovalent, Reversible Bruton's Tyrosine Kinase Inhibitor (BTKi), Vecabrutinib, in B-Lymphoid Malignancies (ASH 2018) - P1b/2; "Prior therapies included ≥1 chemotherapy regimen (n=9), BTKi (ibrutinib, n=8; acalabrutinib, n=1), venetoclax (n=4), and chimeric antigen receptor T-cell therapy (n=2). The study (NCT03037645) continues enrollment in the dose-escalation phase. Planning is ongoing for subsequent phase 2 expansion cohorts in selected indications."

Clinical • P1/2 data • PK/PD data • Biosimilar • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pain

Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)–CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2019) - P1; "Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing."

Clinical • IO Biomarker • P1 data • PK/PD data • CD38

A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. (PubMed, Cancer Discov) - "Stable disease was sustained for {greater than or equal to}6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors."

CAR T-Cell Therapy • Clinical • Combination therapy • Journal • P1 data • Breast Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • MSLN