IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

Abstract

BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model

“…The dynamic of serum MCP1 concentration change is earlier than the other cytokines, suggesting MCP1 was induced by lymphodepletion rather than CAR T-cell infusion, which is consistent with human study showing that high MCP1 concentration at the time of CAR T-cell infusion correlates with better outcome (37). This observation further supports the relevance of the canine model to clinical study of human CAR T cells (38). Our results in healthy dogs also provide baseline comparison for future patient dog treatment to distinguish immune response against immunotherapy from that against tumor cells.…”

Immunotherapy of sarcomas with modified T cells

“…Endogenous NY-ESO-1 specific T cells have been safely transferred in a phase I trial; however, all patients experienced disease progression and transferred cells lacked markers of proliferation or activation [30,74 ▪ ]. Proliferation was induced when the T cells were cultured ex vivo with IL-15, supporting the evaluation of this cytokine for use following cell infusion to support responses.…”

“…IFNα has been safely utilized in TIL therapy, and IFNγ may indeed have its uses in sensitizing patients to ACT [95], but should be evaluated in the medium – to long term after cell infusion, for example several weeks after or at the time of progression. Ex-vivo application of IL-15 has stimulated activation and proliferation of persisting NY-ESO-1 endogenous T cells supporting its clinical evaluation as a sensitizing agent [74 ▪ ]. Importantly, high dose IL-2 was utilized following cell infusion in early trials of NY-ESO-1-directed TCRs and warrants further consideration once the safety and activity of this approach has been reliably demonstrated [69,70].…”

“…There is a continued lack of consensus on an optimal lymphodepletion regime for ACT with TCR-transduced T cells. Current regimes have evolved following their use in TIL melanoma trials, and from CD19-targeted CAR-T cell therapy [34,74 ▪ ,96,97]. Lymphodepletion augments the antitumor effect of transferred cells by eliminating endogenous suppressor T-cell populations and competition for cytokines including IL-7 and IL-15.…”

Trial watch: chemotherapy-induced immunogenic cell death in oncology

“…Finally, they concluded that durvalumab together with anthracycline-/taxane-based neoadjuvant chemotherapy (NACT) was the most optimal treatment regime for increased pCR rates. Additionally, more advanced molecular analysis such as RNA sequencing was also often used as biomarker discovery 242 , 265 , 266 . For instance, Pusztai et al (Yale Cancer Center, New Haven, CT, USA) found while investigating paclitaxel in combination with durvalumab and the poly-ADP ribose polymerase (PARP) inhibitor olaparib in breast cancer that their dendritic cell signature had a positive correlation with pCR in the treatment arm 267 .…”