Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors

Abstract

Purpose: To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors.

Materials and methods: Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT + ACT (n = 10), HT + ACT + anti-PD-1 inhibitor (pembrolizumab) (n = 11) and HT + ACT + CT (n = 12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.

Results: The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR = CR + PR + SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders (p < 0.05) while IL-6 and IL-10 were elevated among those with progressive disease (p < 0.05). Peripheral blood CD8⁺/CD28⁺ T cells increased (p = 0.002), while the CD4⁺/CD25⁺/CD127⁺Treg cells decreased after therapy (p = 0.012). TCR diversity was substantially increased among the clinical responders.

Conclusions: Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.

KEYWORDS:

• Hyperthermia
• safety
• T cell receptor repertoire
• adoptive cell therapy
• ovarian cancer
• pancreatic cancer

Disclosure statement

The authors who have taken part in this study declare that they have nothing to disclose regarding funding or conflict of interest with respect to this manuscript.

Additional information

Funding

This work was supported by Enhancement Funding of Beijing Key Laboratory for Therapeutic Cancer Vaccines 2019-JS01, Beijing Shijtan Hospital, Capital Medical University Cancer Center.