847 CF33-CD19t oncolytic virus (onCARlytics) in combination with off-the-shelf allogeneic CyCART-19 T cells targeting de novo CD19+ solid tumors

Park, Anthony; Monroy, Isabel; Cook, Colin; He, Shiwen; Karasiewicz, Kathy; Shah, Mubarak; Withana, Nimali P.; Chong, Leslie; Hariri, Robert; Fong, Yuman; Priceman, Saul J.

doi:10.1136/jitc-2022-sitc2022.0847

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“…P-T CD19 CAR-T secretes lower IFN-γ and TNF-α, and our data demonstrate CD4 + P-T CD19 CAR-T favor IL-2 production over IFN-γ. We observed similar findings in solid tumor models comparing P-T CD19 CAR-T to PBMC-CD19 CAR-T. 44 Other studies demonstrated that T N/SCM versus bulk T cells have enhanced antitumor responses while also reducing the risk of severe cytokine release syndrome (CRS) in CD19-targeted murine models. 45 Lower IFN-γ levels may help mitigate toxicity without compromising antitumor activity 46 as IFN-γ blockade reduces macrophage-mediated cytokines associated with CRS without impacting CAR-T efficacy or persistence.…”

Section: Discussionsupporting

confidence: 83%

Placental circulating T cells: a novel, allogeneic CAR-T cell platform with preserved T-cell stemness, more favorable cytokine profile, and durable efficacy compared to adult PBMC-derived CAR-T

Ruggeri Barbaro,

Drashansky,

Tess

et al. 2024

J Immunother Cancer

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BackgroundChimeric antigen receptor (CAR)-T cell quality and stemness are associated with responsiveness, durability, and memory formation, which benefit clinical responses. Autologous T cell starting material across patients with cancer is variable and CAR-T expansion or potency can fail during manufacture. Thus, strategies to develop allogeneic CAR-T platforms including the identification and expansion of T cell subpopulations that correspond with CAR-T potency are an active area of investigation. Here, we compared CAR-T cells generated from healthy adult peripheral blood T cells versus placental circulating T (P-T) cells.MethodsCAR-T cells from healthy adult peripheral blood mononuclear cells (PBMCs) and P-T cells were generated using the same protocol. CAR-T cells were characterized in detail by a combination of multiparameter flow cytometry, functional assays, and RNA sequencing. In vivo antitumor efficacy and persistence of CAR-T cells were evaluated in a Daudi lymphoma xenograft model.ResultsP-T cells possess stemness advantages compared with T cells from adult PBMCs. P-T cells are uniformly naïve prior to culture initiation, maintain longer telomeres, resist immune checkpoint upregulation, and resist further differentiation compared with PBMC T cells during CD19 CAR-T manufacture. P-T CD19 CAR-T cells are equally cytotoxic as PBMC-CD19 CAR-T cells but produce less interferon gamma in response to lymphoma. Transcriptome analysis shows P-T CD19 CAR-T cells retain a stem-like gene signature, strongly associate with naïve T cells, an early memory phenotype, and a unique CD4 T cell signature compared with PBMC-CD19 CAR-T cells, which enrich for exhaustion and stimulated memory T cell signatures. Consistent with functional data, P-T CD19 CAR-T cells exhibit attenuated inflammatory cytokine and chemokine gene signatures. In a murine in vivo model, P-T CD19 CAR-T cells eliminate lymphoma beyond 90 days. PBMC-CD19 CAR-T cells provide a non-durable benefit, which only delays disease onset.ConclusionWe identified characteristics of T cell stemness enriched in P-T CD19 CAR-T which are deficient in PBMC-derived products and translate into response durability in vivo. Our findings demonstrate that placental circulating T cells are a valuable cell source for allogeneic CAR-T products. Stemness advantages inherent to P-T cells translate to in vivo persistence advantages and long-term durable activity.

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Section: Discussionsupporting

confidence: 83%