cesnicabtagene autoleucel (ARI0002h)

P2, N=15, Not yet recruiting, Cell and Tissue Therapies WA, Royal Perth Hospital, East Metropolitan Health Service

However, this improvement was not significant compared to ARI0002h (p = 0.07). This study failed to demonstrate a significant benefit of TIGIT-blockade on ARI0002h cells despite using three different approaches, suggesting that targeting a single immune checkpoint may be insufficient.

This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized BCMA-directed CAR-T therapy, ARI0002h...These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by day 100 and 180 post-infusion. These findings suggest that metabolites and gut microbiota correlate with CAR-T cell therapy responses and can be a valuable tool for risk assessment.

Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.

We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase I clinical trial (CARTD-BG-01, NCT06097455) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

Lymphodepletion (LD) with cyclophosphamide and fludarabine was used...Tocilizumab and steroids were administered in 68% (mainly for persistent grade 1 CRS) and 30% of pts, respectively... Results from 30 additional pts and a longer follow-up of the first cohort confirm the deep and durable responses obtained with ARI0002h. The booster dose may be partially responsible for the improvement of responses over time and exhaustion may play a role in relapse.

To shed some light on specific transcriptomic programs activated after CAR-T cell administration, we interrogated longitudinal samples of CAR-T cells collected from patients enrolled in CARTBCMA-HCB-01 (NCT04309981) and academic clinical trial in patients with RRMM (Oliver-Caldes A, et al... Overall, our analysis combining scRNA-seq/scTCR-seq with novel machine learning models, allowed us to characterize key transcriptional differences observed between patients, infusion products and in vivo infused CAR-T, as well as between CAR-T according to their location (PB vs. BM). Importantly, our results identify IL10 as a regulatory mechanism promoting CAR-T cell dysfunction, representing a potential target to be modulated for the development of improved CAR-T therapies for MM.

To shed light on the potential mechanisms driving CAR-T cell persistence we performed longitudinal transcriptomic analysis, at single cell level, of CAR-T cells from a patient enrolled in CARTBCMA-HCB-01 clinical trial (NCT04309981) (Oliver-Caldes A, et al... Our analysis clearly showed that most CAR-T cells after administration presented expression of key markers related to T cell memory and survival without clonal expansion, suggesting that memory induction is crucial for long-term persistence. Interestingly, prior to tumor relapse, we observed reactivation of CAR-T cell with the enrichment of effector and activation signatures, and GRN analysis identified FOS and NR4A2 regulons as potential drivers involved in CAR-T cell reactivation. Overall, scRNA-seq/scTCR-seq coupled with novel machine learning models provides relevant mechanistic insights that could uncover useful targets to be modulated for the development of long-term persistent CAR-T cells.

ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach.

At our institution, we have developed an academic BCMA-BBζ CART product (ARI2h; NCT04309981) for relapsed/refractory MM patients with encouraging results... This is the first bispecific BCMA/CD229 CART cell that adequately controls BCMA-expressing and non-expressing myeloma cells. This approach could mitigate disease escape due to biallelic loss of BCMA.

CAR-T cells were FACS-isolated from infusion products (IP) as well as from bone marrow (BM) and peripheral blood (PB), at different times after cell infusion (1 and 3 months), from three MM patients enrolled in the academic clinical trial assessing ARI0002h... Overall, our data show that multiomic analysis are useful tools to characterize CAR-T cell dynamics after infusion, that presented different characteristics regarding their location (PB vs BM) and a heterogeneous behavior within the patients. Moreover, GRN analysis at single cell level offers an important tool to understand mechanisms modulating CAR-T cell response and to identify possible mechanisms of relapse.

Our In-house developed CARs targeting CD19 (ARI0001) and BCMA (ARI0002h) have proven safe and efficacious in the treatment of patients with B-cell malignancies and multiple myeloma, respectively. Here we present co-transduction as a feasible strategy to obtain dual CD19/BCMA CAR-T cells. ARI0003 responds better to lower CD19 levels than ARI0001 and presents advantages compared to the bicistronic strategy in terms of efficacy and to the pool in terms of time and cost of manufacturing. Our studies provide strong pre-clinical data to test ARI0003 dual-CAR-T cells in clinical trials to treat NHL patients.