Adoptive T Cell Therapy Using Antigen-Specific CD8+ T Cells for the Treatment of Patients with Cancer: A Phase I Clinical Study.

Abstract

The adoptive transfer of in vitro induced and expanded tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherpy of cancer. We have previously shown that antigen-specific CTL can be generated from HLA-A2.1+ cancer patients by 4 rounds of in vitro stimulation of purified CD8+ T cells with autologous dendritic cells pulsed with HLA-A2 binding tumor-associated peptides. Based on these results we have initiated a pilot study of adoptive T cell therapy in advanced melanoma patients demonstrating that in vitro generated Melan-A (ELAGIGILTV)-specific CTL survive intact in vivo for several weeks and localize preferentially to tumor. Here we report on the clinical results of a phase I study of 11 HLA-A2+ melanoma patients that received at least three i.v. infusions of Melan-A-specific CTL i.v. at 2-week intervals. Each T cell infusion was accompanied by a 6-day course of s.c. IL-2 (3x106 IU daily). A total of 51 T-cell infusions were administered, averaging 2.1 x108 Melan-A specific T cells per infusion, with a range from 0.11 – 13.1 x108 T cells per infusion. Clinical side effects were mild and consisted of chills and low-grade fever (WHO grade I–II) in 7 out of 11 patients that typically occurred within 6 to 8 h post infusion. Hematological effects, observed after T cell transfer, included an increase in eosinophils up to 50% in 7 out of 11 patients, peaking 24h post transfer. Clinical and immunological responses consisted of antitumor responses in 3 out of 11 patients (1 CR, 1 PR, 1 mixed response), an elevated frequency of circulating Melan-A multimer+ T cells up to 2% of total CD8+ T cells for 2 weeks post T cell infusion, suggesting long-term survival and/or proliferation of transferred CTL, and a complete loss of Melan-A expression in lymph node metastases of 2 patients after T cell transfer. Our data indicate that the adoptive transfer of antigen-specific T cells in cancer patients is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects.

Therapeutic cancer vaccines: are we there yet?

“…From a practical standpoint, co-administration of an antigen-specific vaccine in combination with ACT requires knowledge of the reactivity contained in the transferred T-cell population. This may be possible when the transferred T cells are mono-specific by design, such as T cells genetically engineered to express a single exogenous T-cell receptor (TCR) (126,127) or a cloned population of T cells raised against a defined epitope (114,128,129). In the case of TILs, however, provision of an antigen-specific vaccine at the time of cell infusion can prove technically challenging, if not impossible.…”

“…This is an especially critical problem, as optimization of the in vivo function of TILs remains a high priority. In contrast with other sources of T cells for ACT, such as cloned T cells (114,128,129,131) or T cells engineered to express exogenous TCRs reactive against shared melanoma ⁄ melanocyte antigens (126,127), TILs appear to be capable of mediating durable cancer regression in a larger frequency of patients with relatively less toxicity to host tissues (20,21). Recent experiments in mice have demonstrated at least two potential solutions to solve this problem by providing mimetics for vaccination that act in an antigenindependent manner.…”