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1973 PD-1 Inhibitor Combinations As Salvage Therapy for Relapsed/Refractory Multiple Myeloma (MM) Patients Progressing after Bcma-Directed CAR T Cells

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Diseases, multiple myeloma, Biological, Adult, Therapies, CAR-Ts, checkpoint inhibitors, Biological Processes, Technology and Procedures, Plasma Cell Disorders, immunotherapy, Study Population, Lymphoid Malignancies, Clinically relevant, immune mechanism
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Luca Bernabei1*, Alfred L. Garfall, MD2, J. Joseph Melenhorst, PhD3, Simon F Lacey, PhD, BS3, Edward A. Stadtmauer, MD, FACP2*, Dan T. Vogl, MD4, Vanessa Gonzalez5*, Gabriela Plesa, MD5*, Regina M Young, PhD3*, Adam Waxman, MD4,6, Bruce L Levine, PhD3, Carl H June, MD3, Michael C. Milone, MD, PhD7 and Adam D. Cohen, MD4

1Division of Hematology Oncology, University of Pennsylvania, Philadelphia, PA
2Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
3Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
4Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
5Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA
6Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
7Center for Cellular Immunotherapies, Perelman School of Medicine At the Univ. of Pennsylvania, Philadelphia, PA

Background: Autologous T cells expressing a chimeric antigen receptor (CAR) specific for B-cell maturation antigen (CART-BCMA cells) show activity in refractory MM, but relapses remain common. Anti-PD-1 antibodies (Abs) augment CAR T cell activity pre-clinically, and induced CAR T cell re-expansion and responses in DLBCL patients progressing after CD19-specific CAR T cells (Chong et al, Blood 2017). The IMiDs lenalidomide (len) and pomalidomide (pom) may enhance efficacy, but also toxicity, of both CAR T cells and PD-1 inhibitors in MM. Elotuzumab (elo) has clinical anti-MM activity in combination with IMiDs and dexamethasone (dex), and synergizes with anti-PD-1 Ab in pre-clinical models.

Methods: We previously described outcomes of 25 subjects enrolled on our phase 1 study of CART-BCMA cells in relapsed/refractory MM (Cohen et al, ASH 2017, #505). We identified and retrospectively reviewed 5 subjects who progressed after CART-BCMA and received a PD-1 inhibitor (pembrolizumab (pembro)) combination as their next therapy. Responses were assessed by IMWG criteria. CART-BCMA levels were assessed by flow cytometry and qPCR pre-treatment, 2-4 weeks after first pembro dose, then q4 weeks until progression. Pembro dosing was 200mg every 3 weeks; dex dosing was 20-40mg/week.

Results: Characteristics of the 5 subjects are in the Table. Median prior lines was 9; all had high-risk cytogenetics. All were refractory to pom, 2 to pembro/pom/dex, and 1 to elo. Best response to CART-BCMA was PR in 2, MR in 2, and PD in 1. Median time from CART-BCMA to pembro-based therapy was 117 days. All patients still had CART-BCMA cells detectable by qPCR, with 2 (pts. 07 and 21) still detectable by flow, at initiation of salvage therapy. The first pt. (02) received pembro/pom/dex and had MR but progressed at 2 months, with no detectable CART-BCMA re-expansion. The second pt. (07) had rapidly-progressing kappa light chain MM 2 months post-CART-BCMA and had previously progressed on pembro/pom/dex. He started elo/pembro/pom/dex and had MR at day 12 (free kappa 1446 to 937 mg/L), associated with robust expansion of CART-BCMA cells (875.64 to 20505.07 copies/µg DNA by qPCR; 0.7% to 6.4% of peripheral CD3+ cells by flow). Re-expanded CART-BCMA cells were predominantly CD8+ and highly activated (89% HLA-DR+, up from 18% pre-therapy). This response was short-lived, however, with progression 1 week later, and return of CART-BCMA levels to baseline at week 5. Three subsequent subjects then received elo/pembro/dex with either len or pom; with 2 MR and 1 SD, and PFS of 3 to 4 months. None had re-expansion of CART-BCMA cells. Non-specific immune modulation was observed and included altered CD4:CD8 T cell ratio (n=5), increased NK cell/decreased T cell frequency (n=4), and HLA-DR upregulation on CAR-negative T cells (n=2). More detailed phenotyping of CART and other immune cells, including PD-1 expression, is ongoing. With regard to toxicity, pt. 02 had self-limiting low-grade fevers and myalgias 4 weeks after pembro/pom/dex, associated with mild elevation in ferritin/CRP, suggestive of mild CRS. No other CRS was noted, including pt. 07 despite CART-BCMA re-expansion. One patient (17) developed recurrent expressive aphasia starting 2 months after elo/pembro/pom/dex, without signs of CRS and no observed expansion of CART-BCMA cells in blood or CSF. This resolved with stopping therapy and brief steroid taper.

Conclusions: This study demonstrates that a PD1-inhibitor combination can induce CAR T cell re-expansion and anti-MM response in a MM patient progressing after CART-BCMA therapy. Since this patient previously progressed on pembro/pom/dex, the observed clinical activity was likely related to the CAR T cells, with elotuzumab also possibly contributing. However, this effect was very transient; re-expansion occurred infrequently (1/5 patients); and neurotoxicity was observed (though its relationship to the CAR T cells is unclear). This makes it difficult to endorse this specific salvage regimen. Nonetheless, this proof-of-principle observation suggests that a subset of patients may respond to checkpoint blockade or other immune-modulating approaches following BCMA CAR T cell therapy, meriting further study.

Disclosures: Garfall: Kite Pharma: Consultancy; Novartis: Research Funding; Amgen: Research Funding; Bioinvent: Research Funding. Melenhorst: novartis: Patents & Royalties, Research Funding; Incyte: Research Funding; Shanghai UNICAR Therapy, Inc: Consultancy; Casi Pharmaceuticals: Consultancy; Parker Institute for Cancer Immunotherapy: Research Funding. Lacey: Parker Foundation: Research Funding; Tmunity: Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties; Novartis Pharmaceuticals Corporation: Research Funding. Stadtmauer: Janssen: Consultancy; AbbVie, Inc: Research Funding; Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Vogl: Karyopharm Therapeutics: Consultancy. Plesa: Novartis: Research Funding. Young: Novartis: Patents & Royalties, Research Funding. Levine: Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; Incysus: Consultancy; Cure Genetics: Consultancy; CRC Oncology: Consultancy; Brammer Bio: Consultancy. June: Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding. Milone: Novartis: Patents & Royalties. Cohen: Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Kite Pharma: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy.

*signifies non-member of ASH