Despite currently available chemotherapy regimens, patients with relapsed diffuse large B cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) have a very poor prognosis and represent an area of unmet need. For this reason, novel approaches are needed for this patient population. One novel approach currently being investigated in the clinical setting is the adoptive transfer of T cells genetically modified to express artificial T cell receptors termed chimeric antigen receptors (CARs) designed to recognize target antigens expressed on the tumor cell surface. To this end, a patient?s own T cells may be isolated and through retroviral or lentiviral gene transfer modified to express the CAR thereby redirecting T cell specificity to the tumor associated antigen. Most B cell malignancies, including most B cell non-Hodgkins lymphomas (NHL), chronic lymphocytic leukemias (CLL) and B cell acute lymphoblastic leukemias (B-ALL) express the B cell specific antigen CD19. Significantly, most DLBCLs similarly express the CD19 antigen. To date we and several other groups have recently reported initial clinical outcomes of patients with both low grade as well as aggressive B cell cancers treated with CAR T cells targeted to the CD19 antigen. To date, these clinical studies have reported anti-tumor responses in patients with low grade B cell CLL and far more markedly in patients with relapsed/refractory B-ALL. More recently, clinical outcomes of a small cohort of patients with relapsed DLBCL treated with CD19 targeted CAR T cells have demonstrated promising but suboptimal responses, with 4 of 7 patients demonstrating complete remissions (CRs) but only 3 of 4 responses being relatively durable (9-22 months) with relatively short follow-up. An additional and relevant immune-based approach to cancer therapy, having only recently demonstrated moderate clinical benefit in the setting of DLBCL after autologous bone marrow stem cell transplantation, is immune-checkpoint blockade through infusion of antagonistic MAb?s targeted to the T cell PD-1 receptor, which when engaged to either the PD-L1 or PD-L2 ligand induces T cell anergy. As a result, blockade of this T cell checkpoint pathway with PD-1 specific MAbs may in turn enhance the anti-tumor function of tumor targeted T cells and may further modulate an otherwise immune suppressive tumor microenvironment to one more suitable for immune targeted tumor eradication by both CAR T cells as well as recruited endogenous anti-tumor immune effectors. The primary goal of this project is to optimize CD19 targeted CAR T cell therapy in patients with DLBCL. To this end in Aim 1 we will initially apply our CD19 targeted 19-28z CAR T cell approach to very poor prognosis elderly relapsed/refractory ASCT ineligible DLBCL patients, a condition representing an unmet medical need, in a phase I/II clinical trial as a single agent therapy following salvage chemotherapy.
In Aim 2 we utilize a clinically relevant immune competent murine model of DLBCL to investigate the rationale of combining 19-28z CAR T cell therapy with PD-1 checkpoint inhibition wherein the latter immune-based approach may protect the CD19 targeted CAR T cells from PD-L1 and PD-L2 mediated anergy or apoptosis and favourably modulate the tumor microenvironment. Finally, in Aim 3 of this proposal we will translate these studies back into the clinical setting in a planned second phase I/II clinical trial targeting the same patient population designed to optimize the anti-tumor efficacy with 19-28z CAR T cell therapy combined with PD-1 immune checkpoint blockade.

Public Health Relevance

Most elderly patients with relapsed/refractory DLBCL are not be eligible for the potentially curative stem cell transplant, either due to age (half of the patients with DLBCL are older than 65 years) and /or presences of comorbid medical conditions. The goal of this proposal is to improve the cure rate of older patients with relapsed DLBCL by exploring novel cell-based immune therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA192937-05
Application #
9988855
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2016-08-30
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141
Pasqualucci, Laura; Dalla-Favera, Riccardo (2018) Genetics of diffuse large B-cell lymphoma. Blood 131:2307-2319
Joshi, Suhasini; Wang, Tai; Araujo, ThaĆ­s L S et al. (2018) Adapting to stress - chaperome networks in cancer. Nat Rev Cancer 18:562-575
Kishinevsky, Sarah; Wang, Tai; Rodina, Anna et al. (2018) HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nat Commun 9:4345
Rafiq, Sarwish; Yeku, Oladapo O; Jackson, Hollie J et al. (2018) Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol 36:847-856
Lu, Xiaoqing; Fernando, Tharu M; Lossos, Chen et al. (2018) PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival. Blood 132:2026-2039
Kaittanis, Charalambos; Andreou, Chrysafis; Hieronymus, Haley et al. (2018) Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors. J Exp Med 215:159-175
Liu, Yuxuan; Mondello, Patrizia; Erazo, Tatiana et al. (2018) NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proc Natl Acad Sci U S A 115:12034-12039
Intlekofer, Andrew M; Joffe, Erel; Batlevi, Connie L et al. (2018) Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay. Blood Cancer J 8:60
Guo, A; Lu, P; Lee, J et al. (2017) HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene 36:3441-3449

Showing the most recent 10 out of 28 publications