Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy

Abstract

Purpose: Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods: We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results: Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions: Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

Keywords: Dendritic cells; Herpes Simplex Virus; T cell receptor sequencing; oncolytic viral therapy.

Figure 1.

(A) Kaplan–Meier curves for progression free survival and overall survival for the OrienX010 dose escalation trial. The median PFS was 16.3 mo (497 d). Median OS has not been met. (B) Kaplan–Meier curves for progression free survival and overall survival for the DC–CIK therapy expansion trial. The median PFS was 9.9 mo (301 d). Median OS has not been met.

Figure 2.

(A) Metastatic melanoma baseline CT of right submandibular (SM) met pre-OrienX010, (B) SM met post-OrienX010, and (C) SM met s/p after three cycles of DC -CIK therapy. (D) Malignant thymoma baseline CT of mediastinal mass (MM) pre-OrienX010, (E) MM after OrienX010, and (F) MM after two cycles of DC -CIK therapy. (G) Metastatic breast cancer baseline CT of left breast (LB) mass before OrienX010, (H) LB mass after OrienX010, and (I) LB mass after one cycle of DC -CIK therapy.

Figure 3.

Clone populations in TCR β repertoires. (A) Schema for patient 401 tracks clone populations over time and b/w OrienX010 and DC–CIK treatments: purple clones first appear in the baseline sample, orange in the post-ORIEN sample, green in the pre-DC–CIK, and blue in the post-DC–CIK. (B) Patients 401, 506, 602, 603, and 604 received both OrienX010 and DC–CIK therapy, whereas patients 402, 403, 501, and 504 received OrienX010 only.