Tumor-infiltrating lymphocytes

TILs are implicated in killing tumor cells. The presence of lymphocytes in tumors is often associated with better clinical outcomes (after surgery or immunotherapy).^[6][7][8][9]

Detection and characteristics

TILs can be found between the tumor cells, as TILs in the stroma surrounding the tumor cells do not count.

They are key to an experimental autologous cell therapy (Contego) for metastatic melanoma.^[15] Autologous TIL therapy for metastatic melanoma has broad T cell recognition of both defined and undefined tumor antigens against all human leukocyte antigen (HLA) restrictions. TILs can not only recognize over-expressed self/melanocyte differentiation antigens, such as Melan-A/MART-1 (melanoma-specific), gp100, tyrosinase, and survivin, but TILs can also recognize other unknown antigens specific to the tumor and individual patient.^[16]

Use in adoptive T cell transfer therapy

History

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]

Process

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]

Clinical Success

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

• Lymphocyte
• Tumor-Infiltrating Dendritic Cell
• Cancer Immunotherapy
• CAR T-Cell therapy
• T-cells

References