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654 Early Signals of Anti-Tumor Efficacy and Safety with Autologous CD5.CAR T-Cells in Patients with Refractory/Relapsed T-Cell Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Allogeneic CARs and CARs for T Cell Lymphomas
Hematology Disease Topics & Pathways:
Biological, Lymphomas, Chimeric Antigen Receptor (CAR)-T Cell Therapies, T Cell Lymphoma, Clinically Relevant, Diseases, Therapies, Lymphoid Malignancies
Monday, December 13, 2021: 11:45 AM

Rayne H. Rouce, MD 1, LaQuisa C. Hill, MD1, Tyler S. Smith2*, Lina Yang, PhD1*, Blakely Boriskie3*, Madhuwanti Srinivasan3*, Huimin Zhang, BS1*, Silvana Perconti, MS1*, Birju Mehta3*, Olga Dakhova, PhD3*, Bambi J. Grilley, RPh1*, Helen E. Heslop, MD, DSc1, Malcolm K. Brenner, MD, PhD1* and Maksim Mamonkin, PhD4

1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX
2Texas Tech University Health Sciences Center, El Paso, TX
3Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX
4Center for Cell and Gene Therapy, Center For Cell and Gene Therapy, Houston, TX

Introduction

We present results of a Phase I clinical trial (NCT03081910) of autologous T-cells expressing a CD5-specific chimeric antigen receptor (CD5.CAR) as therapy for refractory or relapsed (r/r) mature T-cell lymphoma (TCL). T-cells expressing an optimized second-generation, CD28-costimulated CD5.CAR resist fratricide by rapidly degrading CD5 protein and expand normally ex vivo. We evaluated the feasibility of manufacturing autologous CD5.CAR T-cells from patients with r/r peripheral or cutaneous TCL and the safety of these CD5.CAR T-cells as a bridging therapy to allogeneic hematopoietic stem cell transplant (alloHSCT). We also assessed anti-tumor activity and kinetics of in vivo expansion and persistence of CD5 CAR T-cells as well as their off-tumor activity against normal circulating T-cells.

Methods and patient characteristics

CD5.CAR T-cells were manufactured from PBMC using gammaretroviral transduction of T-cells following anti-CD3/anti-CD28 stimulation. Fourteen patients were enrolled, and we have treated nine patients (age 27-71, median 63) with mature TCL including cutaneous TCL (n=2), angioimmunoblastic TCL (AITL, n=2), peripheral TCL (n=4), and adult T-cell leukemia/lymphoma (n=1). All patients were eligible for alloHSCT and had an available donor. Median number of prior lines of therapy was 5 (2-18), and 5 patients had relapsed after autologous (n=3) or allogeneic HSCT (n=2).

Results

All patients received autologous CD5.CAR T-cells on one of three dose levels: two on dose level 1 (1x107 CAR T cells/m2), four on dose level 2 (5x107 CAR T cells/m2), and three on dose level 3 (1x108 CAR T cells/m2). Seven patients received a single dose of CD5.CAR T-cells following lymphodepleting chemotherapy (LDC) with cyclophosphamide and fludarabine, and two patients received an additional dose following initial disease evaluation. One patient received a 2nd course of LDC prior to re-infusion. CD5.CAR T-cells expanded and persisted in all patients for up to 9 months , peaking in peripheral blood at 1-4 weeks post-infusion (Fig. 1). CD5.CAR T-cell infusions were associated with a transient reduction in peripheral T-cell counts but depletion was incomplete as circulating normal T-cells were detected in most patients over the follow-up period. No severe infections were observed. Max grade CRS and ICANS was grade 2, which occurred concurrently in one patient and promptly resolved following treatment. Three patients experienced grade 1 CRS and no other neurotoxicity events were observed. The most frequent treatment related adverse events were cytopenias which recovered to baseline within 28 days in all but 3 patients, in one of whom cytopenias extended beyond day 56. The remaining grade 3 events were primarily non-hematologic laboratory abnormalities which returned to baseline or improved during the monitoring period.

Reponses were evaluated 4-6 weeks post-infusion. Four out of nine patients (44%) achieved responses, enabling three to proceed to alloHSCT. Complete responses were obtained in two patients, one with AITL and one with peripheral TCL. Another patient with AITL achieved a mixed response followed by a second infusion of CD5.CAR T-cells and subsequently proceeded to alloHSCT. A very good partial response was achieved in a patient with HTLV-1 driven ATLL (Fig. 2). Two patients remain alive and in CR for 29 months and 24 months respectively. The remaining patients experienced stable disease (n=1) or progressive disease (n=4). Clinical responses were observed on all dose levels.

Objective responses did not correlate with cell dose or magnitude of T-cell expansion. All responses were obtained with CD5.CAR T-cell products produced with a shortened manufacturing method in which CAR T-cells were cryopreserved 3-5 days post-transduction instead of undergoing a standard 7-day expansion. Shortened manufacturing resulted in an enrichment of minimally differentiated CCR7+ CD62L+ T-cells (27-fold mean increase in CD4+, 13-fold increase in CD8+; p=0.01) and a 3.5-fold increase in CD27+ CD8+ T-cells (p=0.04) suggesting minimizing duration of ex vivo expansion increases anti-tumor function of CD5.CAR T-cells.

Overall, these results show that even in patients with multiply relapsed/resistant TCL, CD5.CAR T-cells can produce anti-tumor responses that are sufficiently durable to enable them to proceed with alloHSCT without inducing clinically significant T-cell aplasia.

Disclosures: Rouce: Tessa Therapeutics: Research Funding; Pfizer: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hill: Incyte: Membership on an entity's Board of Directors or advisory committees. Grilley: Allovir: Current equity holder in publicly-traded company, Other: Leadership; QB Regulatory Consulting: Other: Ownership, project management support, Research Funding; Marker: Consultancy, Other: Regulatory and project management support. Heslop: Allovir: Current equity holder in publicly-traded company; Gilead: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Current equity holder in publicly-traded company; Takeda: Membership on an entity's Board of Directors or advisory committees; Fresh Wind Biotherapies: Membership on an entity's Board of Directors or advisory committees; Kuur Therapeutics: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Brenner: Walking Fish Therapeutics: Membership on an entity's Board of Directors or advisory committees; CellGenix GmbH: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Current equity holder in publicly-traded company; Tessa Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Abintus: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Athenex: Membership on an entity's Board of Directors or advisory committees; Memgen: Membership on an entity's Board of Directors or advisory committees; Turnstone Biologics: Membership on an entity's Board of Directors or advisory committees; Coya Therapeutics: Membership on an entity's Board of Directors or advisory committees; TScan Therapeutics: Membership on an entity's Board of Directors or advisory committees; Onkimmune: Membership on an entity's Board of Directors or advisory committees; Poseida Therapeutics: Membership on an entity's Board of Directors or advisory committees; Allovir: Current equity holder in publicly-traded company. Mamonkin: Xenetic Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene Therapeutics: Consultancy, Other: Licensing payments; Beam Therapeutics: Other: Licensing payments; Fate Therapeutics: Other: Licensing payments.

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