Abstract 48: T cell-specific in vivo transduction with preclinical candidate KLN-1010 generates BCMA directed CAR T cells with potent anti-multiple myeloma activity

Abstract

Abstract Introduction: Multiple Myeloma (MM) is the second most diagnosed hematologic malignancy and remains an incurable disease. KLN-1010 is a novel treatment for MM currently in preclinical development that uses our iGPSTM platform, an envelope-modified lentiviral vector particle engineered for specific and efficient in vivo gene delivery, to transduce T cells. T cells modified in vivo by KLN-1010 express a fully human anti-BCMA CAR following a single IV injection without the need for additional treatments or conditioning chemotherapy. Results: Human T cells exposed to KLN-1010 in vitro resulted in transduction and expansion of anti-BCMA CAR T cells in a concentration dependent manner. The resulting CAR T cells were highly avid and specific to BCMA-expressing cell lines. KLN-1010 treatment of preclinical mouse models resulted in T cell-specific CAR expression with no evidence of off-target modification including in the lung and liver, except phagocytes. A varied CAR T cell lineage composition was observed that included effector and memory CD4 and CD8 T cells. A single dose of KLN-1010 caused potent anti-tumor efficacy and complete tumor regression in a stringent model that requires high dose levels of ex vivo-cultured CAR T cells similar to those commercially available. When the anti-BCMA CAR molecules used in KLN-1010 are compared in preclinical models to other clinically relevant CARs, we observed superior tumor control by the KLN-1010 anti-BCMA CAR molecules. Clinical application of iGPS technology was modeled in non-human primates (NHP) using an NHP T cell-targeting particle that expresses an anti-CD20 CAR. CAR T cell activity, assessed by B cell depletion, and tolerability were evaluated without prior lymphodepleting chemotherapy across a 10x dose range. Rapid clearance of the iGPS particles from the blood was observed at all dose levels. Even at a low dose of 1.3e8 IU/kg, potent and durable CAR T cell activity was observed as evidenced by complete B cell depletion lasting over two months. Multiple CAR T cell expansions and contractions were observed during this period. The treatment at all dose levels was highly tolerable with no observed toxicities, cytokine release syndrome, or neurotoxicity. Conclusions: These data demonstrate that KLN-1010 is safe and efficacious in preclinical models and may offer greater accessibility than other therapeutic modalities to address an unmet medical need in MM. Without requirements of ex vivo manufacturing, lymphodepletion and inpatient treatment that restrict patient access to therapy, the iGPS technology is well poised to provide significant clinical benefit for a multitude of indications as an off-the-shelf, single dose treatment. Citation Format: Emily T. Beura, Howard J. Latimer, Denise Wong, Jenifer Obrigewitch, Alyson J. Warr, Shirley Dong, Matty Ariel, Josue Figueroa, Joseph Figueroa, Connor S. Dobson, Sanath K. Janaka, Alexander J. Najibi, Maggie Lau, Shannon Contrastano, Kevin Friedman. T cell-specific in vivo transduction with preclinical candidate KLN-1010 generates BCMA directed CAR T cells with potent anti-multiple myeloma activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 48.