T cell responses in the microenvironment of primary renal cell carcinoma

Background

Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) is based on the infusion of T cells isolated and expanded from tumor lesions of the individual patients. This treatment can induce unprecedented rates of durable complete responses in metastatic melanoma. The aim of this study was to characterize TILs from primary renal cell carcinoma (RCC), in order to initiate a clinical trial testing TIL therapy for patients with RCC. Preliminary data on TIL expansion were previously presented at ESMO Symposium on Immuno-Oncology 2015 (1). Here, final results of expansion, functional characterization and comparison with T cell responses in melanoma are presented.

Methods

Primary tumor lesions from 25 patients with RCC scheduled for radical or partial nephrectomy were collected. TIL were isolated and expanded from tumor fragments with standard methods derived from clinical trials of melanoma. Autologous tumor cell lines were established from the same lesions and used as killing-targets for TILs.

Results

TIL cultures from primary RCC were successfully generated and expanded to clinical numbers from 23 of 25 (92%) samples. Expanded TILs showed phenotypic characteristics similar to melanoma, with >95% T cells and a considerably variable CD4/CD8 ratio. CD8⁺ T cell responses against autologous tumor cell lines were detected in 11 of 15 RCC patients (73%) where an autologous RCC cell line was available. Tumoricidal capacity was confirmed with cytotoxicity assays. However, both frequency and magnitude of CD8⁺ T cell responses were significantly higher in melanoma. Multidimensional characterization of three types of functional T cell responses revealed a unique pattern of anti-tumor reactivity of RCC-TIL compared to melanoma.

Conclusions

TILs from RCC specimens can be isolated and expanded to clinical numbers. Tumor-recognition in vitro can be demonstrated for the majority of samples. However, immune responses of expanded CD8⁺ TILs from RCC are on average weaker than in melanoma and display a unique functional pattern, typical of heavily exhausted immune cells. 1) Andersen R. et al. Preclinical development of adoptive cell therapy with tumor-infiltrating lymphocytes for patients with renal cell carcinoma. Annals of Oncology (2015) 26 (suppl_8): 5-14.

Clinical trial identification

Legal entity responsible for the study

Herlev Hospital

Funding

Herlev Hospital

Disclosure

All authors have declared no conflicts of interest.