An advance in adoptive T cell therapy is the ability to endow patient's T cells with reactivity for tumor cell surface molecules through the introduction of genes that encode synthetic chimeric antigen receptors (CARs). Studies of small numbers of patients with advanced B cell malignancies have demonstrated potent antitumor effects of T cells that express a CD19-specific CAR in a subset of patients, suggesting this approach could provide a major advance in therapy. However, not all patients respond and the duration of response remains uncertain. Prior studies have not rigorously defined the phenotypic composition or frequency of CAR T cells administered to patients, which has resulted in variations in potency and in vivo persistence, and could explain the lack of efficacy in many patients. Our group has focused on elucidating cell intrinsic properties of human T cells that provide for reproducible in vivo behavior after genetic modification and adoptive transfer, and on optimizing the design of CARs for tumor recognition and safety. We initiated the first clinical tril of CD19 CAR- T cell therapy in which the T cell products administered to every patient were formulated in a defined optimized composition. The initial results have revealed profound tumor regressions in patients with advanced chemotherapy refractory NHL after infusion of small doses of CD19 CAR-T cells. This proposal will build on these accomplishments and develop CD19 CAR T cell therapy into a reproducible, broadly effective and safe therapy for B cell malignancies.
The specific aims are:
Aim 1. To evaluate the safety, antitumor efficacy, and mechanisms of tumor escape after adoptive transfer of CD19 CAR-T cells administered in a defined cell product composition in patients with refractory B cell lymphoma or leukemia.
Aim 2. To evaluate the safety and durability of antitumor responses of CD19 CAR-T cells derived from TM cells for therapy of ALL and CLL after HLA matched related or unrelated allogeneic HCT.
Aim 3 : To perform a phase I clinical trial to determine if adoptively transferred CD19 CAR-T cells that co-express a truncated human EGFR can be deleted in vivo by infusion of the anti-EGFR mAb, Erbitux.
Immunotherapy is emerging as a new and effective modality for cancer therapy. One of the most promising approaches is to engineer the patient's T cells to express a synthetic receptor that instructs the T cell to seek out and eliminate cancer cells. The studies in this application focus on translating this approach into a reproducible and safe therapy for patients with leukemia and lymphoma.
|Gust, Juliane; Hay, Kevin A; Hanafi, Laïla-Aïcha et al. (2017) Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discov 7:1404-1419|
|Gardner, Rebecca A; Finney, Olivia; Annesley, Colleen et al. (2017) Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129:3322-3331|
|Hay, Kevin A; Hanafi, Laïla-Aïcha; Li, Daniel et al. (2017) Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood 130:2295-2306|
|Turtle, Cameron J; Hay, Kevin A; Hanafi, Laïla-Aïcha et al. (2017) Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. J Clin Oncol 35:3010-3020|
|Sommermeyer, D; Hill, T; Shamah, S M et al. (2017) Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 31:2191-2199|
|Pollack, Seth M; He, Qianchuan; Yearley, Jennifer H et al. (2017) T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer 123:3291-3304|
|Hay, Kevin A; Turtle, Cameron J (2017) Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies. Drugs 77:237-245|
|Sadelain, Michel; Rivière, Isabelle; Riddell, Stanley (2017) Therapeutic T cell engineering. Nature 545:423-431|
|Paszkiewicz, Paulina J; Fräßle, Simon P; Srivastava, Shivani et al. (2016) Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 126:4262-4272|
|Liu, Lingfeng; Sommermeyer, Daniel; Cabanov, Alexandra et al. (2016) Inclusion of Strep-tag II in design of antigen receptors for T-cell immunotherapy. Nat Biotechnol 34:430-4|
Showing the most recent 10 out of 44 publications