T-Cell Receptor Gene Therapy for Human Papillomavirus–Associated Epithelial Cancers: A First-in-Human, Phase I/II Study

Abstract

PURPOSEGenetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)–associated epithelial cancers.METHODSThis phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin.RESULTSTwelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient’s resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell–mediated antitumor activity. Another patient’s resistant tumor demonstrated loss of HLA-A*02:01, the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation.CONCLUSIONEngineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

“…As NK cells detect and eliminate tumor cells via MHC- and antigen-independent mechanisms, NK cell-based immunotherapy may overcome some mechanisms of resistance to T cell-based immunotherapy, including selection of tumor subclones lacking antigen or harboring antigen processing/presentation defects (reviewed in (23)). The presence of genomic alterations in one or more of these antigen processing and presentation pathways predicts response to all forms of T cell-based immunotherapy including immune checkpoint blockade and adoptive transfer cell therapies(3-6). Most existing data has explored whole tumor biopsies for the presence of one or more of these genomic alterations and correlation to response to immunotherapy.…”

“…Through selective immune pressure during tumorigenesis and progression and genomic instability, subpopulations of tumor cells acquire mutations that lead to defective type II interferon (IFN) responses and altered antigen processing and presentation(1, 2). The presence of these mutations predicts failure to respond to immune checkpoint blockade and adoptive T cell transfer immunotherapy(3-6).…”

CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies

“…Prophylactic HPV vaccines have no therapeutic effect on established disease, thus HPV infections are expected to continue contributing to the global cancer burden (5). Recent studies suggest that HPV þ cancers may be successfully targeted with T-cell therapy, wherein adoptive transfer of tumor-infiltrating or genetically engineered T cells was shown to induce responses in HPVassociated cancer patients (6)(7)(8). These studies provide proof of concept that a therapeutic strategy that increases the frequency of tumor antigen specific T cells may be sufficient to drive clinical benefit in this population.…”

Application of Droplet Digital PCR for the Detection of Vector Copy Number in Clinical CAR/TCR T-Cell Products

“…T cells engineered to express TCRs directed to the cancer/testis antigen NY-ESO-1 TCRs are being used to treat melanoma and synovial cell sarcoma [7]. Recently, TCR engineered T cells directed to Human Papilloma Virus (HPV) 16 E6 oncoprotein have been used treat HPV-associated epithelial cancers [8].…”