Efficacy-enhanced and cytokine release syndrome-attenuated anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

Abstract

Chimeric antigen receptor-T cell (CAR-T) therapy in T cell malignancies faces fratricide, T cell aplasia, and product contamination. Here, we successfully developed a universal anti-CD7 CAR-T product (RD13-01). RD13-01 contains a bbzg-CAR comprising an anti-CD7 single-chain variable fragment, a 4-1BB costimulatory domain, a CD3ζ signaling domain, the intracellular domain of the common γ chain, and a natural killer cell inhibitory molecule (E-cadherin). TRAC, CD7 and HLA-II were disrupted to avoid graft versus host disease (GvHD), fratricide and rejection. Bbzg-CAR-T exerted antitumor effects superior to those of conventional CAR-T, while exhibiting reduced cytokine production. Among 11 evaluable relapsed/refractory (r/r) patients, no dose-limited toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade≥3) occurred. Nine (82%) showed objective response. For r/r leukemia and NHL, complete response rates were 75% and 33.3% respectively. Outstanding safety and efficacy of this universal CAR-T product was achieved in CD7+ T cell malignancies.

CD7 targeted “off-the-shelf” CAR-T demonstrates robust in vivo expansion and high efficacy in the treatment of patients with relapsed and refractory T-cell malignancies

“…The short persistence is considered to be an advantage to prevent T-cell aplasia but also a disadvantage to prevent cancer recurrence 3 . Interestingly, less than 4 weeks of CAR-T cell persistence is adequate for majority of patients to reach MRD-CR in both studies 20 . 3 patients treated with GC027 maintained PFS > 6 months with a single infusion (Fig.…”

“…Theoretically, the likelihood of CAR + leukemia cells in autologous CAR-T products is higher in T malignancies, especially with approaches to reduce fratricide. Huang at al have recently reported clinical data on a similar allogeneic, universal CD7 CAR-T approach to GC027, but the two products were enhanced by different cytokine receptors 20 . Huang et al introduced a γc portion to the CAR intracellular domain and observed rescue of IL-2 production and enhanced proliferation20.…”

“…5B). Notably, serious infection and patient death were observed in both autologous and allogeneic studies 17,20,21 , which suggest that short term de ciencies in CD7 + T and NK cells potentially lead to life threatening infections, and intensi ed patient care with prophylactic use of anti-viral medicine and antibiotics should be considered in the future studies.…”

“…"Off-the-shelf", allogeneic CAR-T targeting CD7 are not expected to have a long lifespan because they will be eliminated upon immune reconstitution of CD7-T cells in the host 3,4,20 . In the two reported CD7 targeting "off-the-shelf" approaches, CAR-T cells persist less than 4 weeks in majority of the patients 4,20 . The short persistence is considered to be an advantage to prevent T-cell aplasia but also a disadvantage to prevent cancer recurrence 3 .…”