UCART19

To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell secretome analysis revealed that CD2 deletion in UCART19 reduced frequencies of the effector cytokines (Granzyme-B and IFN-γ). Treatment with rhIL-7-hyFc prolonged UCART2 persistence and increased survival in both the tumor re-challenge model and primary patient T-ALL model in vivo. Together, these data suggest that allogeneic fratricide-resistant UCART2, in combination with rhIL-7-hyFc, could be a suitable approach for treating T-cell malignancies.

Simulations from the final model recapitulated UCART19 expansion rates in the clinical trial, confirmed the need for alemtuzumab to observe UCART19 expansion (along with fludarabine cyclophosphamide), quantified the importance of allogeneic elimination, and suggested a high impact of multipotent memory T-cell subpopulations on UCART19 expansion and persistence. A mathematical mechanistic pharmacokinetic/pharmacodynamic model supports and captures quantitatively the beneficial impact of lymphodepleting patients before the infusion of an allogeneic CAR-T cell product. Mediation through IL-7 increase and host T lymphocytes decrease is underlined, and the model can be further used to optimize CAR-T cell therapies lymphodepletion regimen.

All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection. First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

In this study, we conducted a Non-viral Genome Targeting approach for producing the allogeneic anti-CD19 CAR-T cells (nvGT UCART19), SC-U02...Tocilizumab was administered during CRS for this patient, and the symptom was reversed afterwards...However, due to limited cases reported, SC-U02’s safety and efficacy profile still needs to be decided. The research is ongoing and 6×10 8 cell dose level will be assessed later on.

All patients were pretreated for lymphodepletion by fludarabine + cyclophosphamide before CAR-T infusion. The CAR-T provided were axicabtagene ciloleucel (Yescarta, Kite/Gilead, n=16, tisagenlecleucel (Kymriah, Novartis Pharma, n=5 and brexucabtagene autoleucel (KTE-X19, Tecartus, Kite/Gilead, n=1). One additional patient received allogeneic UCART19 (Servier)...The two patients in relapse and treated by chemotherapy or tafasitamab did not develop antibodies after V2 conversely to the patient under maintenance by revlimid... This study shows that the administration of two doses of BNT162b2 anti-SARS-CoV-2 messenger RNA vaccine provides a low rate of seroconversion (30%) in recipients of CAR-T therapy. This is likely related to the profound B-cell depletion induced by this treatment precisely targeting CD19+ cells. Investigation of the development of specific T-cell responses in these individuals could provide more information about the efficacy of vaccination in this context.

P1, N=13, Completed, Institut de Recherches Internationales Servier | Recruiting --> Completed | Trial primary completion date: Jan 2021 --> Sep 2020

P1, N=25, Completed, Institut de Recherches Internationales Servier | Recruiting --> Completed

P1, N=18, Recruiting, Institut de Recherches Internationales Servier | N=12 --> 18 | Trial completion date: Jul 2020 --> Jan 2021 | Trial primary completion date: Jul 2020 --> Jan 2021 | Active, not recruiting --> Recruiting

To create anti-CD19 universal CARTs (UCART19) and anti-CD2 CARTs (UCART2), we activated human T cells on CD3/CD28 beads, electroporated the T cells with Cas9 mRNA, a TRAC-targeted gRNA, and, in the case of UCART2, a CD2-targeted gRNA, and virally transduced CAR against the target antigen containing a peptidase 2A-cleaved human CD34 construct for both purification and tracking in vivo. Specifically, NT-I7 can dramatically enhance gene-modified T cell proliferation, persistence, and tumor killing in vivo, resulting in enhanced survival, thus providing a tunable clinic-ready adjuvant for reversing suboptimal CART activity in vivo. Funding NIH/NCI Leukemia SPORE P50 CA171063–01, NIH/NCI Outstanding Investigator Award R35 CA152329 Siteman Innovators Award, NIH/NCI AML P01 CA101937, Siteman Innovator Award, Children's Discovery Institute.