Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL

Abstract

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable tumor from which (2) TIL can be generated that (3) exhibit tumor-specific reactivity. From July 2002 to July 2007, 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from tumors that were larger in diameter and digests that had a higher percentage of lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation.

FIGURE 1.

Surgical metastasectomy within the Surgery Branch, NCI from July 2002 to 2007. Every tumor was recorded and exclusions criteria were applied as described. Each remaining specimen was processed for fragment-derived cultures, digest-derived cultures, or both. A tumor was considered positive for growth if at least 1 fragment-derived or digest-derived culture met criteria (fragment 313, digest 35, both 329). Similarly, a tumor was considered active based on interferon-γ enzyme-linked immunosorbent assay as described (fragment 210, digest 50, both 162). Of the 107 patients treated, 63 were treated with cells derived from fragments only, 10 from digests only, and 34 from a mixture of digest-derived and fragment-derived tumor infiltrating lymphocyte.

FIGURE 2.

Analysis of tumor size and digest characteristics on tumor infiltrating lymphocyte (TIL) growth and tumor reactivity. A, Tumors that generated viable and tumor-reactive TIL had longer mean diameters than those tumors that either did not generate TIL or generated nonreactive TIL. B, The likelihood of successful TIL growth (left) and tumor recognition (right) is shown as a function of the HLA-A2 allele and tumor size. C, Success rates for growth (left) and antitumor reactivity (right) segregated by percentage of infiltrating lymphocytes and presence of the HLA-A2 allele. D, Success rates for growth (left) and antitumor reactivity (right) as a function of lymphocyte infiltration in digests derived from nodal and non-nodal tissue.