Abstract 4979: Development of KITE-585: A fully human BCMA CAR T-cell therapy for the treatment of multiple myeloma

Abstract

Background: Multiple myeloma (MM) is a usually fatal malignancy of plasma cells, with no current therapy considered curative. About 15% of patients diagnosed with MM are stratified as high risk with poor treatment outcomes and short (2-3 years) survival from diagnosis. Standard risk patients tend to live longer but undergo chronic and/or high intensity therapy and likely experience a relapsing and remitting disease pattern. Therefore, there is still a considerable unmet need for innovative therapies that improve outcomes in MM. One such approach is to use adoptive transfer of engineered autologous T cells expressing a chimeric antigen receptor (CAR) directed against malignant cells. The efficacy of CAR T cells directed against hematological malignancies, particularly CD19-expressing B cell leukemia and lymphomas, has been demonstrated in multiple clinical studies. KITE-585 was developed as a CAR T cell immunotherapy product candidate directed against B cell maturation antigen (BCMA). BCMA is nearly ubiquitously expressed on MM cells, plasma cells and subsets of mature B cells, but with limited or absent expression on other tissues. Methods: We generated >50 fully human IgGs directed against BCMA using the BCMA protein as antigen and selection criteria including affinity, cross-reactivity and poly-specificity. Following assessment of the binding of the IgGs to a MM cell line known to express BCMA, >10 IgGs were identified that met the criteria for affinity and selectivity and had a >50-fold binding over background. The 8 IgGs that demonstrated the highest specific binding were then sequence-converted to single-chain variable fragments (scFvs) and incorporated into CARs. Results: In all but one case, human T cells engineered to express these CAR constructs exhibited specific cytolytic activity against MM cell lines (NCI-H929 and MM.1s). These CAR T cells demonstrated killing efficiencies of >95% at effector:target ratios of 1:1 over a 24-hour period. Similarly antigen-specific production of inflammatory cytokines was observed in response to target cell lines in vitro. Assessment of antigen-dependent proliferation over a 5 day period revealed >80% proliferation in the 7 constructs that showed cytolytic activity in vitro. Multiple different anti-BCMA CAR constructs representing distinct epitope binding bins of BCMA were then selected for in vivo evaluation. In two disseminated tumor models of luciferase labeled NCI-H929 or MM.1s cells injected intravenously (i.v.), a single i.v. injection of anti-BCMA CAR T-cells delayed the progression of disease and significantly increased survival when compared to control treatment. Conclusions: The results of these studies highlight the potential of targeting BCMA with adoptive transfer of engineered T cells for the treatment of MM. Given these positive findings, progress towards Phase 1 clinical studies in MM patients with KITE-585 is continuing. Citation Format: Gregor B. Adams, Jun Feng, Atefah Ghogha, Armen Mardiros, Jodi Murakami, Tammy Phung, Ruben Rodriguez, Stuart Sievers, Tassja J. Spindler, Jed Wiltzius, Clare Yarka, Sean C. Yoder, Tony Polverino. Development of KITE-585: A fully human BCMA CAR T-cell therapy for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4979. doi:10.1158/1538-7445.AM2017-4979

VEGFR2-specific FnCAR effectively redirects the cytotoxic activity of T cells and YT NK cells

“…The vast majority of the scFv-based CARs tested in clinical trials are murine or humanized. The recent development of fully human scFv-based CARs against several hematological [ 38 – 40 ] and solid [ 41 , 42 ] cancer cell targets has proven effective in animal models and warrants the exploration of alternative scaffolds based on the human sequences as antigen-recognition modules in CARs. Fn3s represent one such option.…”

BCMA-targeted immunotherapy for multiple myeloma

“…KITE-585 is a second-generation lentiviral-transduced CAR-T cell product which has a fully human anti-BCMA scFv, a CD28 co-stimulatory domain, and a CD3ζ activation domain. KITE-585 demonstrated potent in vitro and in vivo activity against MM cell lines even in the presence of soluble BCMA and also eradicated xenografted MM tumors in mice [141,142]. A first-inhuman, open-label, multicenter phase 1 study (NCT03318861) has been planned to evaluate the safety and feasibility of KITE-585 in R/R MM patients [143].…”

An Overview of CAR T Cell Mediated B Cell Maturation Antigen Therapy

“…It exhibits effective in prelinical studies against multiple myeloma cell lines even in the presence of sBCMA. It also exterminated xenografted multiple myeloma tumours in murine model [101,102]. A phase one open-label, clinical trial in human was proposed (NCT03318861) to investigate the shielding and feasibility of KITE-585 in patients with refractory/relapsed multiple myeloma [103].…”