PHE885 CAR T Cells Show Expansion and Persistence in Multiple Myeloma

Durcabtagene autoleucel (PHE885) chimeric antigen receptor (CAR) T cells were produced in under 2 days, showed response, and demonstrated rapid expansion in vivo and long-term persistence in patients with relapsed/refractory multiple myeloma, according to data presented at the International Myeloma Society 20th Annual Meeting and Exposition.¹

Using the T-Charge platform, the B-cell maturation antigen (BCMA)-targeted CAR T cells were produced, and correlative analysis was performed in 31 patients with heavily pretreated multiple myeloma at Dana-Farber Cancer Institute in a phase 1 study (NCT04318327).

“This CAR T cell is manufactured in less than 2 days using the T-Charge platform, which is much shorter than the conventional CAR T cell manufacturing process,” explained Shuntaro Ikegawa, MD, PhD, a research fellow at Dana-Farber Cancer Institute, during his oral abstract presentation.

Whereas traditional CAR T cells undergo expansion ex vivo for 7 to 10 days before infusion, durcabtagene autoleucel is infused earlier with a lower dose and expansion takes place in patients, which Ikegawa said may promote or preserve T-cell stemness and their function.

Investigators in the phase 1 dose expansion study previously reported positive efficacy and safety results at the 2023 American Society for Clinical Oncology Annual Meeting from 46 patients.2 The patients were able to proceed from apheresis to lymphodepletion in a median of 16 days, and only 28% required bridging therapy due primarily to the quick production time.

At a data cutoff of March 28, 2023, 31 patients treated at Dana-Farber Institute with a median age of 65 years had received doses ranging from 2.5 × 106 to 20 × 106 T cells.1 Ninety-four percent of patients had triple-class refractory multiple myeloma. Twenty-six patients (84%) had received prior hematopoietic stem cell transplant.

All patients responded except for 1 patient who received the lowest dose level, for an overall response rate of 97% including a stringent complete response rate of 38.7%, very good partial response rate of 38.7%, and partial response rate of 19.4%.

Investigators analyzed CAR T-cell kinetics of fresh blood from all patients by flow cytometry, and also analyzed the apheresis sample, CAR T-cell final product, and post-infusion peripheral blood mononuclear cell by mass cytometry and T-cell sequence from the first 15 patients, including 4 who received 2.5 × 10⁶ cells, 10 who received 5 × 10⁶ cells, and 1 who received 14.3 × 10⁶ cells.

“All patients showed robust CAR T-cell expansion which peaked on day 14, and at the time of peak expansion, most patients’ CAR T cells were presenting more than 50% of the circulating T cells,” said Ikegawa.

Some patients continued to show a high number of circulating T cells in the peripheral blood at 1 year or later. CAR T cell expansion was associated with inflammatory cytokine elevation, which Ikegawa said was consistent with other reports on CAR T expansion.

Investigators also measured soluble BCMA level from baseline and in the post-infusion period. In 22 patients who were followed for more than 9 months, 11 had longer CAR T cell persistence had lower levels of soluble BCMA, suggesting that they maintained their functional activity against BCMA over this period.

Apheresis samples were compared with the final CAR T cell product; CD3 stemlike memory T cells (Tscm) increased and CD3 naïve T cells decreased, suggesting that the T-Charge process caused this shift during manufacturing.

Comparing the T cell diversity between Tscm cells and memory cells in the final product showed it was more heterogeneous in the Tscm cells in the CAR T final product for both CD4 and CD8. After infusion of the CAR T cells, CAR positive T cells had higher diversity than CAR negative T cells in CD4 T cells and CD8 T cells.

The T-cell receptor repertoire of post-infusion CAR positive T-cells also appeared to be more similar to Tscm repertoire than the memory T cells in the produced CAR T cells in both CD4 and CD8, suggesting that they were derived from the Tscm cells from the CAR T cell product.

“These CAR T cells exhibit robust expansion in vivo followed by long-term persistence in 50% of the patients, and long-term persistence of CAR positive T cells was associated with suppression of soluble BCMA,” concluded Ikegawa.

_References

_{1. Ikegawa S, Prabhala RH, Sperling AS, et al. Robust in vivo expansion and long-term persistence of anti-BCMA CAR T cells, PHE885, manufactured in < 2 days on the T-Charge platform. Presented at: International Myeloma Society 20th Annual Meeting and Exposition; September 27-30, 2023; Athens, Greece. OA-06.}

_{2. Sperling AS, Derman BA, Nikiforow S, et al. Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM). J Clin Oncol. 2023;41(16_suppl):8004. doi:10.1200/JCO.2023.41.16_suppl.8004}