Minimally Cultured Tumor-infiltrating Lymphocytes Display Optimal Characteristics for Adoptive Cell Therapy

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 appl...

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Bibliographic Details
Published in:	Journal of immunotherapy (1997) Vol. 31; no. 8; pp. 742 - 751
Main Authors:	TRAN, Khoi Q, JUHUA ZHOU, DURFLMGER, Katherine H, LANGHAN, Michelle M, SHELTON, Thomas E, WUNDERLICH, John R, ROBBINS, Paul F, ROSENBERG, Steven A, DUDLEY, Mark E
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott 01-10-2008 Philadelphia,PA
Subjects:	Antineoplastic agents Biological and medical sciences Cell Culture Techniques Cell Line, Tumor Cytokines - immunology Cytotoxicity, Immunologic - immunology Dermatology Humans Immunotherapy Immunotherapy, Adoptive Lymphocyte Activation - immunology Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - transplantation Medical sciences Melanoma - immunology Melanoma - therapy Pharmacology. Drug treatments Telomere - physiology Tumors of the skin and soft tissue. Premalignant lesions Cell culture interleukin-2 Cell therapy Cytokine tumor-infiltrating lymphocyte melanoma Tumor infiltrating lymphocyte Malignant tumor Telomere adoptive cell therapy Adoptive transfer Treatment Interleukin 2 Immunotherapy Malignant melanoma Cancer
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Summary:	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 immunologic assays. We show here that limitations in reagents and methods during screening underrepresent 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 with in 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 uses 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 that, if effective in vivo, may facilitate the widespread application of this approach to a broader population of patients with melanoma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1524-9557 1537-4513
DOI:	10.1097/cji.0b013e31818403d5