BAFF-R CAR T cell therapy for ALL

BAFF-R CAR T 细胞疗法治疗 ALL

• 批准号: 10610931
• 负责人: IBRAHIM ALDOSS
• 金额: $ 66.41万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-18 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610931
• 关键词: Acute; Address; Adult; Affect; Aftercare; Alternative Therapies; Antigen Receptors; Antigens; Autoimmune Diseases; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Neoplasm; B-Lymphocytes; CAR T cell therapy; CD19 Antigens; CD19 gene; CD22 gene; Cell Survival; Cell physiology; Child; Childhood; Cities; Clinical; Clinical Trials; Correlative Study; Cyclic GMP; Data; Data Analyses; Development; Disease; Dose; Down-Regulation; Enrollment; Epitopes; FDA approved; Failure; Fc Receptor; Generations; Genetic Engineering; Hematologic Neoplasms; Human Engineering; Immune; Immunotherapy; In Vitro; Interleukin 4 Receptor; Kinetics; Laboratory Research; Lentivirus; Ligands; Lymphoblastic lymphoma; Lymphoid Cell; Lymphoma; Lymphoma cell; Manuscripts; Modeling; Monoclonal Antibodies; Multiple Myeloma; NK cell therapy; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Phase; Phenotype; Population; Preparation; Principal Investigator; Prognosis; Property; Recommendation; Recurrent disease; Refractory; Relapse; Remission Induction; Reporting; Research; Research Institute; Resistance; Route; Specificity; Surface; T cell therapy; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic Effect; Therapeutic Research; Translating; Treatment Efficacy; Tumor Escape; alternative treatment; bench to bedside; bi-specific T cell engager; cancer cell; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical efficacy; clinical lot; cytokine; effective therapy; experience; first-in-human; high risk; improved; in vivo; innovation; manufacture; mouse model; new therapeutic target; novel; novel therapeutics; patient derived xenograft model; patient population; preclinical study; prevent; professor; response; safety assessment; success; targeted treatment; timeline; tumor

PROJECT SUMMARY B-cell acute lymphoblastic lymphoma (B-ALL) is a neoplasm of B-cell lymphoid precursors that typically affects children, but occurs in adults as well. While intensive multi-agent chemotherapy is highly effective in the pediatric population, outcomes remain poor in adults and high-risk patients. The recent introduction of blinatumomab and CD19-directed CAR T therapy has transformed the care of patients with relapsed and refractory (r/r) B-ALL. However, an increasing number of reports describe a high rate of post-treatment relapse due to acquired resistance to these immunotherapies, notably via down-regulation or loss of CD19 surface expression. CAR T cells that were recently developed against another target, CD22, showed similar shortcomings with relapses associated with diminished antigen expression. The search for alternative targets is therefore essential to overcoming antigen escape. To address this issue, we have developed CAR T cells against a new B-ALL target, the B-cell activating factor receptor (BAFF-R). BAFF-R is a marker of B cells that is also functionally expressed in B-ALL, including in patients with CD19-negative relapse. Although one of BAFF-R’s ligands (BAFF) has been successfully targeted for the treatment of autoimmune diseases, we are the first to have developed BAFF-R CAR T cells that are effective against B-cell malignancies in vivo, including in CD19-negative mouse models. Because BAFF-R is a critical regulator of B-cell function and survival, we can expect that the tumor’s ability to escape therapy by down-regulation of BAFF-R will be limited. While we anticipate clinical efficacy of BAFF-R CAR T cell therapy, dual targeting of CD19 and BAFF-R can prevent the emergence of resistance and improve clinical outcomes. Therefore, we are also developing bispecific CD19- BAFF-R CAR T cells that we aim to rapidly translate from the bench to the bedside. In Specific Aim 1, we will evaluate BAFF-R CAR T cell therapy in a first-in-human clinical trial in patients with r/r B-ALL who are ineligible for or have failed prior CD19-directed therapy. The trial, currently open at City of Hope, will use our TN/MEM- derived manufacturing platform, which yields a naïve/memory T-cell enriched T cell product and has shown remarkable efficacy and tolerability in B-ALL. We will conduct extensive correlative studies using cutting-edge technologies, such as assessing the kinetics of the CAR T cells and that of diverse cytokines, therapeutic effect, and potential mechanisms of relapse and antigen escape. In Specific Aim 2, we will establish the therapeutic efficacy of bispecific CD19-BAFF-R CAR T cells against mixed (CD19-negative + BAFF-R- negative) B-ALL tumor models that mimic the heterogenous tumor phenotype leading to resistance. We will also perform extensive testing of cGMP-grade bispecific CD19-BAFF-R CAR T cells that is required prior to submission of an IND application to the FDA. Our proposal addresses the urgent need for new therapeutic options in patients with r/r B-ALL and could also benefit patients with other B-cell malignancies.

项目总结