Tumor-infiltrating lymphocytes

The use of TILs as an adoptive cell transfer therapy to treat cancer was pioneered by Dr. Steven Rosenberg and colleagues at the Surgery Branch of the National Cancer Institute (NCI).[17] Rosenberg and colleagues have conducted clinical trials for more than two decades using TIL adoptive cell therapy for melanoma.[18] TIL adoptive cell therapy is now a routine regimen in centers across the world, including MD Anderson Cancer Center, where the objective response rates originally observed at the NCI have been reproduced.[19][20] Several centers currently have established TIL therapy protocols for the treatment of melanoma, including the MD Anderson Cancer Center in Houston, Texas,[17] Ella Institute in Sheba Hospital, Israel,[19] and Copenhagen University Hospital in Herlev, Denmark.[21][22]

Cancer specific T-cells can be obtained by fragmentation and isolation of tumor infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. The cells are activated and grown prior to transfusion into the recipient (tumor bearer).

In Adoptive T cell transfer therapy, TILs are expanded ex vivo from surgically resected tumors that have been cut into small fragments or from single cell suspensions isolated from the tumor fragments. Multiple individual cultures are established, grown separately and assayed for specific tumor recognition. TILs are expanded over the course of a few weeks with a high dose of IL-2 in 24-well plates. Selected TIL lines that presented best tumor reactivity are then further expanded in a "rapid expansion protocol" (REP), which uses anti-CD3 activation for a typical period of two weeks. The final post-REP TIL is infused back into the patient. The process can also involve a preliminary chemotherapy regimen to deplete endogenous lymphocytes in order to provide the adoptively transferred TILs with enough access to surround the tumor sites. This chemotherapy regimen is given 7 days before the expanded TIL infusion.[17] This involves pretreatment with a combination of fludarabine and cyclophosphamide. Lympho-depletion is thought to eliminate the negative effects of other lymphocytes that may compete for growth factors and decrease anti-tumor effects of the TILs, depleting regulatory or inhibitory lymphocyte populations.[23]

The combination of TILs with a high dose of IL-2 presents multiple clinical trials demonstrating rates near 50% or more patients effectively responding.[24] In summary of TIL therapy clinical trials, TIL therapy was found to induce complete and durable regression of metastatic melanoma. Tumor reduction of 50% or more was observed in about half of patients.[25][20][26][19] Some patients experienced complete responses with no detectable tumor remaining years after treatment.[18] In one clinical trials, among the 93 patients treated with TILs, 19 patients had complete remissions that lasted greater than 3 years.[17]

In a randomized, phase III trial conducted between 2014 and 2022 in Denmark and The Netherlands, researchers found that treatment with TILs was superior to ipilimumab in metastatic melanoma. [27]

Clinical trials using TILs to treat digestive tract cancers, such as colorectal cancer,[28] and cancers associated with the human papilloma virus (HPV), such as cervical cancer,[29] are ongoing. In colorectal cancer, TILs are associated with microsatellite instability cancers, as may be seen in Lynch syndrome.[30] Also, TILs are associated with most effective immune checkpoint inhibitor therapy in GI cancers.[8][9] They are an important prognostic factor in melanoma and higher levels being associated with a better outcome.[31][32][9] TILs are also associated with better outcomes in epithelial ovarian cancer.[7][9]

The use of TILs to treat other tumor types, including lung, ovarian, bladder, and breast, are under investigation.