P-031: Phase I study to evaluate cellular immunotherapy using CS-1 targeting autologous CAR T cells in patients with relapsed and refractory multiple myeloma (RRMM)

Introduction: CAR T cell therapies targeting BCMA have resulted in durable responses, but not curative and options post relapse remain limited. CS-1 receptor belongs to the signaling lymphocytic activation molecule (SLAM) receptor family, promoting cell adhesion and growth. SLAMF7 (CS-1) targeting CAR T has been reported (CARAMBA trial). CS-1 is highly expressed on MM cells, with low expression in NK cells, small T-cell subsets, and no expression on other tissues.

Methods: We developed autologous memory-derived T cells using a self-inactivating lentiviral vector to express a CS1-targeting, hinge-optimized, 41BB-costimulatory CAR [CS1(dCH2)BBζ], as well as a truncated human EGFR. RRMM patients (pts) with ≥ 3 prior lines of therapy containing a proteasome inhibitor, an IMiD, and an anti-CD38 therapy were eligible. Pts received bridging therapy if needed. A single dose of CS-1 CAR T cells with or without lymphodepletion chemotherapy (LDC) was infused. We used the toxicity equivalence range design of Blanchard and Longmate for escalation and de-escalation rules. The primary endpoints were toxicities and activity profile.

Results: A total of 8 pts were enrolled. The median age was 60 (50-72), pts received 7 (5-12) median prior lines of therapy, 4 (50%) had high-risk cytogenetics, and 5 (62%) had extramedullary disease. Grade 3/4 treatment-emergent adverse events related to CS-1 CAR T cells were reported in 5/8 (62%) pts; of these, the most frequent were anemia (62%), Neutropenia (50%) and thrombocytopenia (25%). Cytokine release syndrome was reported in 2/8 (25%) pts, all grade 1/2. Immune effector cell associated Hemophagocytic lymphohistiocytosis-like syndrome (HLH) developed in 2 (25%) pts (grade 3 in pt #443 which was reversible and grade 5 in pt # 340, respectively). Significant CAR expansion was only seen in the pts (#340 and #443) who received Fludarabine (Flu) + Cyclophosphamide (CY) LDC (Table 1).

Table 1. Overview of cell dose, best response, and DLT.

Pts	LDC	CAR T cell dose (million)	Best Response	DLT
340	Flu (30 mg/m2) + Cy (500 mg/m2)	100	PR	Grade 5 HLH
443	Flu (30mg/m2) + Cy (500 mg/m2)	10	PR	Grade 3 HLH
524	None	10	PD
542	None	10	SD
568	None	50	PD
619	None	50	PD
638	Cy (300 mg/m2)	10	PD
674	Cy (300 mg/m2)	10	SD
next cohort	Reduced dose Flu (25 mg/m2) + Cy (300 mg/m2)	10

PD - progressive disease



Conclusions: The first 2 patients treated with full dose LDC had a massive expansion of CAR T cells, likely leading to HLH even though pts achieved PR. Hence the next cohorts were treated with escalation doses without LDC or Cy alone to establish safety. However, efficacy was limited and therefore, we plan to enroll in the next cohort with a reduced dose of LDC with a cell dose of 10 million to induce a lower expansion of CAR T cells.

This study was financially supported by Mustang Bio., U.S.