Adoptive cell transfer therapy

Abstract

Adoptive cell transfer therapy has developed into a potent and effective treatment for patients with metastatic melanoma. Current application of this therapy relies on the ex vivo generation of highly active, highly avid tumor-reactive lymphocyte cultures from endogenous tumor infiltrating lymphocytes or on the genetic engineering of cells using antigen receptor genes to express de novo tumor antigen recognition. When autologous anti-tumor lymphocyte cultures are administered to patients with high-dose interleukin (IL)-2 following a lymphodepleting conditioning regimen, the cells can expand in vivo, traffic to tumor, and mediate tumor regression and durable objective clinical responses. Current investigation seeks to improve the methods for generating and administering the lymphocyte cultures, and future clinical trials aim to improve durable response rates and extend the patient populations that are candidates for treatment.

Figure 1

Persistence of tumor reactive lymphocytes after TIL transfer is evident by FACS analysis of dominant T cell receptor V beta usage (Patients 10, 16 and 21) or tetramer staining (Patient 28). Reprinted from Dudley et al. 2005 (Reference 23).

Figure 2

Rapid and dramatic elimination of bulky melanoma follows cell transfer therapy after lympohodepleting chemotherapy. A: bulky liver disease rapidly regressed in a patient who proceeded to have a complete response and is now disease free more than 57 months after treatment. B: Bulky cutaneous, subcutaneous and visceral metastatic deposits rapidly regressed after a patient received TIL cells following lymphodepleting chemotherapy and 200 cGy whole body irradiation with hematopoeitic stem cell support. The patient has an ongoing partial response more than 16 months after treatment. C: Several examples of brain metastases regressing after TIL administration, as seen for this patient have been observed, suggesting that the brain is not a site of immune privilege from this treatment.