(PA-048) Preclinical Analysis of Ciltacabtagene Autoleucel Combination Strategies with T Cell Bispecifics and Daratumumab to Support Optimization of Clinical Benefit in Myeloma Patients

Ciltacabtagene autoleucel (Cilta-cel) is a multiple myeloma (MM) specific CAR-T cell therapy targeting BCMA. Teclistamab (Tec), and talquetamab (Tal) are MM directed T cell bispecifics (BsAbs) targeting BCMA and GPRC5D, respectively. All three therapies are designed to harness the anti-tumor activity of T cells. Yet, little is known about their use in concert and/or their preferred sequencing to maximize therapeutic benefit. Likewise, little data exist exploring the impact of daratumumab (Dara), a monoclonal antibody targeting CD38, on the efficacy of Cilta-cel. Our work aims to characterize underlying mechanistic interactions between these therapies to potentially inform on their optimal clinical utilization as we push towards regimens with curative intent in MM.


Methods:   We used an in vitro model where healthy donor T cells were exposed to MM cells with either Tec, Tal, or Dara, before or concurrently with research-grade Cilta-cel. See figure legends for details.

Results:   BsAbs induced downregulation of CD28 on T cells and up-regulation of markers associated with T cell exhaustion. Downstream assays using these BsAb pre-exposed T cells revealed diminished expansion and reduced transduction efficiency during the generation of research grade Cilta-cel, and a reduced capacity of the derived CAR-T products to kill MM cells in a serial cytotoxicity assay. Tec and Tal produced similar results, suggesting this effect is BMCA and GPRC5D target agnostic. These data may explain why MM patients with prior BCMA BsAbs had lower response rates and shorter duration of response to BCMA CAR-T. Interestingly, when BsAbs were concurrently added with research-grade Cilta-cel to MM cells, enhanced cytotoxicity synergistically. We also observed increased levels of activation and proliferation of the CAR negative T cells present in the co-culture, along with increased expression of FAS and ICAM-1 on the tumor cells. Finally, addition of Dara, also synergistically enhanced the in vitro cytotoxicity of research-grade Cilta-cel against MM cells. In contrast to BsAbs, Dara was shown to limit the overall expansion of research grade Cilta-cel. However, immunophenotyping data showed that the remaining CAR-T cells exhibited a reduction in frequency of exhausted T cells and CD38+ Tregs, potentially indicating improved T cell fitness

Conclusions:   These preliminary data support careful consideration of the timing of apheresis with respect to treatment with BsAbs, to preserve T cell fitness. They also suggest that Tec, Tal and Dara, may have an important role in bridging and maintenance strategies to enhance the cytotoxic activity of Cilta-cel, if labeling indications permit. Furthermore, these agents may potentially optimize reduced Cilta-cel cytotoxicity resulting from previous BsAb exposure. Ultimately, mechanisms unraveled by this study may help guide trial designs and the development of novel therapeutic regimens, although more investigation will be required.