A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab

Abstract

Purpose: Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab.

Patients and methods: Freshly prepared autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A2.1-positive subjects alone (ESO, NCT02070406) or with ipilimumab (INY, NCT01697527) in patients with advanced sarcoma or melanoma.

Results: Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort. Four out of six patients treated per ESO (66%), and two out of four patients treated per INY (50%) displayed evidence of tumor regression. Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsies via TCR sequencing. Multiparametric mass cytometry of transgenic cells demonstrated shifting of transgenic cells from memory phenotypes to more terminally differentiated effector phenotypes over time.

Conclusions: ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.

Conflict of interest statement

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST: A.R. has received honoraria from consulting with Bristol Myers-Squibb, Amgen, Chugai, Genentech, Merck, Novartis and Roche, is in the scientific advisory board of Advaxis, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Merus and Rgenix, during the conduct of this work was in the scientific advisory board and held stock in Kite-Pharma, and is co-founder of PACT Pharma and Tango Therapeutics. S.H-L. has received consulting fees from Merck, Amgen, Genmab, Bristol Myers-Squibb, Xencor and Vaccinex; research support from Bristol Myers-Squibb, Merck and Vaccinex; and has performed contracted clinical research with Pfizer, Genentech, Astellas, Neon Therapeutics, F Star, Xencor, and Nektar Therapeutics. B.C. has served on the advisory boards for HUYA, Compugen, Array, Regeneron, Iovance, Lilly, Biothera and on speaker bureau for Genentech and Janssen. A.S. has served on the advisory board and Speaker’s Bureau for Eli Lilly, the Speaker’s Bureau for Novartris and OncLive, the advisory board for Daiichi Sankyo, and has served on the board of directors and owns stock in Certis Oncology Solutions. The other authors declare no potential conflicts of interest.

©2018 American Association for Cancer Research.

Figures

Figure 1.. Study overview.

Schedule of events for patients who received NY-ESO-1 TCR transgenic adoptive cell therapy and NY-ESO-1 peptide-pulsed DC vaccination. For patients who received ipilimumab, their dosing schedule (every three weeks) is indicated in parentheses.

Figure 2.. NY-ESO-1 transgenic TCR ACT + DC vaccination with or without ipilimumab produces frequent antitumor responses, but these are generally transient and incomplete.

(A) Pre- and post-treatment PET/CT images from patients showing evidence of initial antitumor activity (decreased FDG uptake) in both ESO and INY cohorts. (B) Swimmer plot showing onset and duration of antitumor activity, as well as progression-free survival and overall survival in all patients in both groups.

Figure 3.. NY-ESO-1 TCR transgenic T cells display peripheral expansion and contraction over time.

Postinfusion peripheral blood levels of NY-ESO-1 TCR transgenic CD3+ cells over time in patients receiving transgenic cells and DC vaccinations alone (ESO, A), or in combination with ipilimumab (INY, B).

Figure 4.. NY-ESO-1 transgenic TCR T cells track to tumor sites.

(A) NY-ESO-1 IHC staining of biopsies from a patient with synovial sarcoma who enrolled on ESO (ESO-5) and, following a partial response, developed progressive disease and enrolled to the INY protocol (INY-3) and experienced a transient response, followed by disease progression. (B,C) Representative IHC sections demonstrating CD8 T cell infiltration and co-localized MHC I expression in the tumor tissue obtained after ESO (B) and INY (C) protocols, both of which had been absent in the baseline tumor tissue. In the progression biopsy obtained after ESO protocol (B), PD-1 and PD-L1 expression was also increased in areas with significant CD8 T cell infiltration in the tumor invasive margin. TCR sequencing showing the relative clonotype frequencies in the TCR repertoire within both biopsies is indicated by the accompanying pie charts, with each slice representing a different TCR clonotype and its frequency. NY-ESO-1 transgenic TCR is highlighted within each chart in cyan.

Figure 5.. Post-infusion phenotypic evolution of NY-ESO-1 transgenic TCR T cells over time.

(A) t-SNE plot of total lineage−/CD3+/TCRVβ13.1+ T cells from all samples overlaid with color-coded clusters. (B) t-SNE plots of total lineage−/CD3+/TCRVβ13.1+ T cells from all samples overlaid with the expression of selected markers. (C) Frequency of T cell clusters displayed on a per-sample basis with mean ± SD (*, ESO d0>d70; o, ESO d70>d0; #, INY d0 > d70; x, INY d70>d0; p reg, CD4 Naïve (N), and CD4 effector, as well as CD8 Naïve (N), Central Memory (CM), Effector Memory (EM), Effector Memory re-expressing CD45RA (EMRA), and Effector. (D) Heat map of median arcsinh-transformed marker expression normalized to a mean of 0 and a SD of 1. Orange indicates relative marker over-expression, blue indicates relative under-expression. The median expression was calculated on single, live, CD45+/CD33−/CD56−/CD19−/CD3+/TCRVβ13.1+ cells from thawed PBMC samples from patients. (E) Relative expression of TIM3 and PD1 on CD3+/TCRVβ13.1+ infusion product (day 0) cells and recovery (day +70) cells in both ESO and INY treatment groups (*, p < 0.05; ***, p < 0.001; ****, p < 0.0001).