Lifileucel: FDA-approved T-cell therapy for melanoma

Extract

The history and evolution of tumor-infiltrating lymphocytes for adoptive cell therapy

The availability of the T-cell growth factor, interleukin-2, was essential to the study of T-cell biology. It became available in recombinant form in 1984¹ and by 1985, it was being applied to the production of antitumor T cells for therapy in murine models. Simply placing enzymatically dispersed murine or human tumors into human IL-2 led to the rapid outgrowth of what have become known as tumor-infiltrating lymphocytes (TIL).² This outgrowth coincided with the rapid destruction of the cocultured tumor cells in vitro, leading to a pure preparation of expanding T lymphocytes. At first, these were empirically tested against tumors in murine models using adoptive cell transfer.³ Brief support with systemic IL-2 was also given with the TIL to enhance their survival in vivo. TIL proved to be highly effective against early micrometastases at lower doses than nonspecific antitumor cells such as lymphokine-activated killer cells (LAK). It was also noted that the addition of high-dose cyclophosphamide or whole-body radiation prior to TIL administration was able to cause the regression of much larger established tumors in mice. Early clinical trials with TIL in patients began in 1988.⁴ These showed that TIL and IL-2 alone had modest activity, but the addition of pretreatment with cyclophosphamide and the later addition of fludarabine to lymphodeplete the recipient could cause durable major regressions in patients with melanoma.⁵