TIL therapy and anti-CTLA4: can they co-exist?

Adoptive transfer of tumor-infiltrating lymphocytes (TIL ACT) is one of the first living immunotherapies to be tested in multiple clinical trials in metastatic melanoma and results consistently in a 40 to 50% overall response rate [1-5]. The majority of these trials were conducted prior to the wide spread use of checkpoint inhibition. Given the ease of administration and favorable response rates, checkpoint inhibitors such as anti-CTLA4 and anti-PD1 have been FDA approved and are now widely used. This has dramatically changed the patient population seeking TIL therapy. In our recent publication, we evaluated the impact of pretreatment with anti-CTLA4 in TIL ACT-treated patients and found that patients that were exposed to this checkpoint inhibitor prior to TIL therapy experienced a reduced clinical response of shorter duration. In addition, patients who were previously exposed to anti-CTLA4 were infused with less TIL than the checkpoint point na？ve patients, suggesting a suboptimal ability of the CTLA4-exposed TIL to expand [6]. Since our previous work had shown that higher number of TIL infused correlated with responses, this observation was of concern [2]. The reduced proliferation occurred only during the rapid expansion protocol (REP) step, where cells are grown in presence of a TCR stimulation. Why would anti-CTLA4 exposed TIL grow less after TCR activation