A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus–associated Epithelial Cancers

Abstract

Purpose Cellular therapy is an emerging cancer treatment modality, but its application to epithelial cancers has been limited. This clinical trial evaluated tumor-infiltrating lymphocyte (TIL) therapy for the treatment of patients with metastatic human papillomavirus (HPV)-associated carcinomas. Experimental Design The trial was a phase II design with two cohorts, cervical cancers and non-cervical cancers. Cell infusion was preceded by a lymphocyte-depleting conditioning regimen and followed by systemic high-dose aldesleukin. Results Objective tumor responses occurred in 5/18 (28%) patients in the cervical cancer cohort and 2/11 (18%) patients in the non-cervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the non-cervical cancer cohort were in anal cancer and oropharyngeal cancer. The HPV reactivity of the infused T cells correlated with clinical response. Peripheral blood repopulation with HPV-reactive T cells also correlated with clinical response. Conclusions/Discussion These findings support the concept that cellular therapy can mediate the regression of epithelial cancers, and they suggest the importance of predictive biomarkers and novel treatment platforms for more effective therapies.

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

“…Efforts to understand the determinants of successful TIL-based therapies have focused on resolving which classes of antigens are recognized by infiltrating T cells in responding patients. These studies have revealed that TIL can recognize a wide spectrum of antigens, including tissue differentiation antigens, 6,168 cancer germline antigens, 12 viral oncoproteins, 12,15 and neoantigens. 5,6,8,[10][11][12]17,169,170 Despite evidence of clinical activity, broad dissemination of TIL therapies has been limited by practical challenges associated with procuring and expanding T cells from surgically obtained samples.…”

“…This is particularly true for patients with modestly mutated cancers arising from epithelial organs, collectively the leading causes of adult cancer‐related deaths . Detailed immune monitoring studies of exceptional patient responders to immunotherapy have revealed three critical variables that simultaneously must be satisfied for cancer regression to occur . First, the patient must possess a repertoire of T cells capable of recognizing antigens displayed on the surface of cancer cells.…”

Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non-small cell lung cancer

“…Recent reports have demonstrated that TIL therapy can deliver a significant reduction in tumour burden in late-stage cancer patients suffering from a diverse set of epithelial tumours as well as melanoma. A response rate of 28% was reported in 18 patients with human papilloma virus (HPV)-related cervical cancer using HPV-targeted T cells [34], two of whom had achieved ongoing durable CRs for over 4 years at the time of the report. In an ongoing study of TIL therapy, a 44% response rate, with two CRs, was observed among 27 patients with advanced recurrent, metastatic or persistent cervical cancer [35].…”

“…KRAS and EGFR mutations are essentially restricted to lung adenocarcinomas, and EGFR mutations are enriched in females and non-smokers [59][60][61]. Notably, the tumour mutation burden is markedly lower in patients with EGFR, ALK, RET or ROS1 mutations [34].…”

Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models

“…Clinical activity has been reported with tumor-infiltrating lymphocytes for melanoma 3 and for human papillomavirus (HPV)-associated epithelial cancers. [4][5][6] T cell receptor genetically engineered T cells (TCR-T cells) have shown clinical activity in melanoma, 7 sarcoma, 7 and HPV-associated epithelial cancers. 8 Nonetheless, despite remarkable tumor responses in patients with these cancers and other epithelial cancers, 9 10 enhanced efficacy remains an important goal in the development of cellular therapies.…”