CTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients.

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an immunoregulatory molecule expressed by activated T cells and resting CD4CD25 T cells. In patients with advanced melanoma, our group reported that administration of anti-CTLA-4 antibody mediated objective cancer regression in 13% of patients. This study also established that the blockade of CTLA-4 was associated with grade III/IV autoimmune manifestations that included dermatitis, enterocolitis, hepatitis, uveitis, and a single case of hypophysitis. Since this initial report, 7 additional patients with anti-CTLA-4 antibody-induced autoimmune hypophysitis have been accumulated. The characteristics, clinical course, laboratory values, radiographic findings, and treatment of these 8 patients are the focus of this report.

Adoptive cell therapy (ACT) with tumor reactive lymphocytes in patients with refractory melanoma can result in tumor regression and prolonged survival. Generating tumor reactive lymphocyte cultures is technically difficult and resource intensive; these limitations have restricted the widespread application of ACT. Tumor infiltrating lymphocytes (TIL) from melanoma contain tumor antigen reactive cells. The “standard” method for producing TIL cultures for clinical administration requires extended in vitro expansion in interleukin-2, then identification of tumor reactive cells by immunological assays. We show here that limitations in reagents and methods during screening under-represent the actual reactivity of TIL cultures. Furthermore, the extended culture times necessitated by the screening assays resulted in telomere shortening and reduced expression of CD27 and CD28 in the TIL cultures, properties that our prior studies showed are correlated within vivo persistence and clinical response. We have thus developed an alternative “young” TIL method that demonstrated superior in vitro attributes compared with standard TIL. This approach utilizes the entire resected tumor to rapidly expand TIL for administration without in vitro testing for tumor recognition. Our observations suggest that younger TIL can have an undetermined but high level of antigen reactivity, and other advantageous attributes such as long telomeres and high levels of CD27 and CD28. We suggest that minimally cultured, unselected lymphocytes represent an alternative strategy for generating TIL cultures suitable for use in ACT therapy that, if effective in vivo, may facilitate the widespread application of this approach to a broader population of patients with melanoma.

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