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.

Patients and methods: The trial was a phase II design with two cohorts, cervical cancers and noncervical 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 of 18 (28%) patients in the cervical cancer cohort and 2 of 11 (18%) patients in the noncervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the noncervical 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: 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.

Fig 1.

Clinical responses in patients after HPV-TIL therapy. (A) Waterfall plot of the maximum change in the sum of target lesions, as compared to baseline measurements, in 29 patients. CR, complete response; PR, partial response; PR, progressive disease; +, stable disease. (B) Spider plots of the change in the sum of target lesions from pretreatment baseline in 29 patients. Black circles (●) indicate ongoing responses, open squares (□) indicate progressive disease due to either a new lesion(s) or increasing target or non-target lesion(s). Black triangle (▼) indicates progressive disease in patient 24 with oropharyngeal cancer due to development of a new brain lesion after a PR of 5 months in duration. (C-D) Contrast-enhanced computed tomography scans obtained at baseline and after treatment for patient 24 with oropharyngeal cancer (C) and patient 26 with anal cancer (D). Tumors are marked by yellow arrows. Patient 24 had disease involving his left lung (first and second row) and mediastinum (third and fourth row). He experienced a PR of 5 months in duration due to a new brain lesion which was surgically excised. He was followed off-protocol, and his target lesions continued to regress, and there was no evidence of disease at most recent follow-up 51 months after treatment. Patient 26 had disease involving both lungs (first and second row). She experienced a PR of 4 months in duration due to increase in her target lesions.

Fig 2.

Human papillomavirus (HPV) reactivity of the infused T cells and peripheral blood T cells after infusion. (A-B) Infused HPV-TILs to 27 cervical and non-cervical cancer patients with HPV16⁺ or HPV18⁺ tumors were assessed for reactivity against HPV type– specific E6 and E7 oncoproteins using (A) CD137 upregulation by flow cytometry, and interferon gamma (IFN-γ) production assays. The HPV-type of each patients’ tumor is provided in Table 1. Patients 10 and 14 had non-HPV16⁺/18⁺ tumors and were not included in this analysis. Values shown represent sum of HPV-type specific E6 and E7 reactivity after background subtraction (gp100). CD137 upregulation is depicted for CD3⁺ T cells. Data are representative of two independent experiments for patients 11 to 13 and 15 to 29, and one experiment for patients 1 to 9 due to unavailability of samples. Peripheral blood (PB) T cells from before and one-month after treatment were assessed by IFN-γ enzyme-linked immunospot assay for reactivity against HPV-type specific E6 and E7 oncoproteins in 22 patients (5 responding and 17 nonresponding patients). Patient numbers are indicated in the parenthesis. Patients 1, 6, 16, 25 and 26 did not have available samples for this analysis. Patients 10 and 14 had non-HPV16⁺/18⁺ tumors and were not included in this analysis. Values shown represent sum of HPV-type specific E6 and E7 spot-forming cells (SFC) after background subtraction (gp100). Eight of 22 patients had discernable HPV reactivity (>20 SFC after background subtraction). Data are representative of two independent experiments patients 11 to 13, 15, 17 to 24 and 27 to 29, and one experiment for patients 2 to 5 and 7 to 9 due to unavailability of samples. CR, responding patient with a complete response, PR, responding patients with a partial response; NR, nonresponding patient.