Disease relapse is a leading etiology of morbidity and mortality for patients with non-Hodgkin lymphoma (NHL) and autologous hematopoietic stem cell transplant following a myeloablative preparative regimen (auto-HSCT) can salvage only a subset of these patients. This Lymphoma SPORE Project 1 renewal resubmission seeks to develop targeted cellular immunotherapy capable of eradicating lymphoma post-transplant minimal residual disease (MRD) using CD19-specific T cell adoptive immunotherapy (AIT). Over the last funding cycle, we developed a genetic engineering approach to equip T cells with the ability to recognize and lyse tumor cells of B-cell lineage NHL using chimeric antigen receptors (CARs) specific for CD19 and initiated a first-in-human pilot clinical trial. Our initial clinical experience revealed a significant obstacle to achieving robust therapeutic activity;namely, that infused T cells survived only transiently in the tumor-bearing recipient. To address this critical issue, we elected to study the fate of adoptively transferred T cells using a non-human primate model that closely recapitulates clinical therapy in humans. These studies have revealed a key insight- that a rare population of T cells present in the circulation, the central memory T cell (TCM). is capable of high-level sustained engraftment following adoptive transfer. Accordingly, we have reconfigured our clinical T cell production platform to immunomagnetically purify CD8+ Tcm from peripheral blood mononuclear cell preparations. These CD8+ TCM then undergo polyclonal activation, lenfiviral vector transduction to express a CD19-specific scFvFc:? CAR, and are expanded over a brief 21-day interval in IL- 2/IL-15 prior to cryopreservation. The first specific aim of the project seeks to demonstrate that CD19RCAR+ CD8+ TcM-derived effector cells from NHL patients are phenotypically and functionally similar to those derived from healthy donors.
The second aim seeks to define the maximum tolerated dose (MTD) of CD19R-CAR+CD8+ TcM-derived effector cells when infused shortly following auto-HSCT (Day +2) when patients with recurrent diffuse large cell lymphoma (DLCL) have minimal disease burdens and are profoundly lymphopenic from the transplant myeloablative preparative regimen. The third specific aim seeks to determine the magnitude and duration of persistence of transferred T cells in treated patients, the ability of transferred effector cells to revert to TMEM and populate memory T cell niches, and the anti-CD19 effector functioning of these cells in patients as determined by tracking the kinetics of CD19+ B cell reconstitution. Lastly, we will seek to demonstrate the exportability of the approach by opening the trial to patient accrual both at the FHCRC in Seattle as well as City of Hope. Each of these Specific Aims focuses on key translational research objectives essential for moving the field of lymphoma AIT forward, including the conduct of a first-in-human trial using central memory T cell adoptive therapy. As such. Project 1 is fully aligned with the SPORE mandate for innovative translational research.
The studies proposed in Project 1 are focused on the development of new immunotherapeutic strategies to eradicate lymphoma MRD following auto-HSCT, a leading cause of morbidity and mortality facing patients with NHL. The technological advances in ex vivo TCM isolation, genetic modification and ex vivo propagation and the knowledge gained from the proposed clinical trial are expected to advance the field of adoptive T cell therapy for lymphoma and human malignancy in general.
|Herrera, Alex F; Rodig, Scott J; Song, Joo Y et al. (2018) Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma. Biol Blood Marrow Transplant 24:514-520|
|Budde, Lihua E; Wu, David; Martin, Daniel B et al. (2018) Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Br J Haematol 183:601-607|
|Herrera, A F; Palmer, J; Martin, P et al. (2018) Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol 29:724-730|
|Zhao, Xingli; Zhang, Zhuoran; Moreira, Dayson et al. (2018) B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors. Mol Ther 26:695-707|
|Adamus, Tomasz; Kortylewski, Marcin (2018) The revival of CpG oligonucleotide-based cancer immunotherapies. Contemp Oncol (Pozn) 22:56-60|
|Herrera, Alex F; Moskowitz, Alison J; Bartlett, Nancy L et al. (2018) Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 131:1183-1194|
|Chen, Robert W; Palmer, Joycelynne M; Tomassetti, Sarah et al. (2018) Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation. J Hematol Oncol 11:87|
|Wang, Xiuli; Walter, Miriam; Urak, Ryan et al. (2018) Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor-Redirected T Cells Against Multiple Myeloma. Clin Cancer Res 24:106-119|
|Mei, Matthew G; Cao, Thai M; Chen, Lu et al. (2017) Long-Term Results of High-Dose Therapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: Effectiveness of Maintenance Rituximab. Biol Blood Marrow Transplant 23:1861-1869|
|Herrera, Alex F; Mei, Matthew; Low, Lawrence et al. (2017) Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation. J Clin Oncol 35:24-31|
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