Author(s): Eytan Ben-Ami aff1 , Jacob Schachter aff1
adoptive cell transfer; immunotherapy; melanoma; tumor-infiltrating lymphocytes
More than 30 years have passed since the isolation and growth of lymphoid cells infiltrating solid tumors, later commonly termed tumor-infiltrating lymphocytes (TILs) [1,2 ].
TILs are found within and can be isolated from various solid tumors (both primary and metastatic lesions). They are composed of a diverse population of immune cells, mainly T cells, a fraction of these T cells express receptors directed against broad but unique tumor-specific mutated antigens (both defined and undefined). These cells have the potential and are at times cytotoxic against malignant cells [3,4 ].
The development of autologous T-cell therapy for metastatic cancers is dependent on the generation of large-scale tumor-specific T cells [ 5 ].
TIL-based adoptive cell transfer requires a fresh tumor tissue
Once a tumor is harvested, autologous TILs are manipulated, expanded ex vivo and then reinfused into the patient, usually with a preconditioning regimen (lymphodepletion) followed by the administration of IL-2.
To date, and for over the past two decades, data published by several groups (including our group) on TIL-based adoptive cell transfer (ACT) therapies have demonstrated ACT to be one of the most powerful immunotherapies, with higher response rates (RRs, 40-72%) and, more importantly, higher durable complete responses (CRs, ˜20%) than other approved agents, including ipilimumab (RR 11%, durable CR 1-2%), anti-PD-1 (RR 35-40%, CR 16%), BRAF inhibitors (RR 50%, CR 6% usually not durable), IL-2 (RR 16%, durable CR 5-6%) and standard chemotherapy (RR less than 15%, rarely durable CRs) [6-8 ].
In spite of accumulating data regarding TIL-based ACT activity and efficacy, this therapy has not been established as a mainstream treatment for metastatic melanoma, probably due to inherent limitations that accompany the process of generating the TILs, and the toxicity of peri-administration treatment.
These limitations include among others a drop out rate of around 30% which is caused either by the inability to grow TIL cultures, or more often, due to the lengthily procedure requiring 5-7 weeks (shorter in 'young' TILs) for the expansion of T cells. This procedure is sometimes associated with clinical deterioration that excludes these patients from continuation to treatment. Furthermore, the peri-administration protocol of TILs which includes a preconditioning regimen (myeloablative chemotherapy regimen with or without total body irradiation) and post TIL administration of high dose IL-2 treatment (characterized by the capillary leak syndrome that usually limits its continuation) is considered by many too toxic.
Furthermore, TIL therapy (or other approved immunotherapies for melanoma such as anti-CTLA-4 or anti-PD-1) does not have surrogate or predictive biomarkers for response and survival. This issue is especially important in ACT TIL-based therapy as the difference in overall survival between complete responders, partial responders and nonresponders could be dramatically high, as reported by Rosenberg et al . (3-year survival for CRs 100%, PRs 31% and nonresponders 7%) and by Besser et al . (3-year survival for responders 78% vs nonresponders 10%) [9,10 ].
Another obstacle to mainstream treatment for metastatic melanoma has been the question...