Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies

Abstract

During the last decade, the field of cancer immunotherapy has been entirely transformed by the development of new and more effective treatment modalities with impressive response rates and the prospect of long survival. One of the major breakthroughs is adoptive cell transfer (ACT) based on autologous T cells derived from tumor-infiltrating lymphocytes (TILs). TIL-based ACT is a highly personalized cancer treatment. T cells are harvested from autologous fresh tumor tissues, and after ex vivo activation and extensive expansion, are reinfused to patients. TIL-based therapies have only been offered in small phase I/II studies in a few centers given the highly specialized care required, the complexity of TIL production and the very intensive nature of the three-step treatment protocol. The treatment includes high-dose lymphodepleting chemotherapy, the infusion of the expanded and activated T cells and interleukin-2 (IL-2) injections to increase survival of the T cells. Despite the limited data on ACT, the small published studies consistently confirm an impressive clinical response rate of up to 50 % in metastatic melanoma patients, including a significant proportion of patients with durable complete response. These remarkable results justify the need for larger clinical trials in other solid tumors, including gynecologic malignancies. In this review we provide an overview of the current clinical results, future applications of TIL-based ACT in gynecologic malignancies, and on risks and challenges associated with modern T cell therapy.

Evaluating different adoption scenarios for TIL-therapy and the influence on its (early) cost-effectiveness

“…It is currently unclear whether such a regimen would be applied soon, but this scenario could influence the cost-effectiveness as TBI (requiring autologous PSC support) would significantly increase the costs. Besides, a very likely scenario that is not incorporated in this analysis, is the use of TIL therapy in other tumors such as renal cell cancer, ovarian cancer, and colorectal cancer [32][33][34][35] (NCT01174121). This scenario should be kept in mind as it may facilitate the adoption of TIL by positively influence the clinicians' attitude as clinical experience and exposure increases, and production costs may decrease.…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…Pre-treating patients with chemotherapy and radiation with resulting lymphodepletion however, increases the persistence and functionality of the transferred cells [ 324 ]. A number of small trials with ACT of autologous TILs in patients with ovarian cancer have been conducted in the past, however, although safe, response rates were variable and not statistically significant [ 325 ]. Improvements to the ACT methodology with solid tumours have been made, such as pre-conditioning with lymphodepletion and T-cell maturation and maintenance with IL-2 infusions, and new ovarian cancer clinical trials utilising the principles learnt are underway [ 325 ], though results are not yet available.…”

Integrating Bioreactor System to Speed Up Tumour Infiltrating Lymphocytes (Tils) Immunotherapy Commercialization

“…It refers to a protocol for TIL expansion that is derived from lymphocytes after TIL extraction step. In this method, unselected lymphocytes are exposed to IL-2, which usually causes expansion to 40-50 millions of total cells within 2-4 w [12]. The resulting bulk of lymphocytes are called "young TILs", which then undergo either CD8 + Subsequent activation step of either CD8 enrichment step using magnetic-beads separation [13], or are directly subjected to activation step [12].…”

“…In comparison with the G-Rex system, which requires almost thirty G-Rex Flasks per patient treatment [14], the package of perfusion system, which can support up to 25 L culture in a single bioreactor [15], is more convenient. GE-WAVE and G-Rex bioreactors were used in scaling up of TILs [14][15][16][20][21][22] and demonstrated impressive clinical results following TILs therapy for melanoma and cervical cancer [12][13][14], which further reinforce the commercial potential of TIL therapy. Further, the Quantum system [17,18], which was used to culture TILs and scale-up CD3 +…”