Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model.

T cell receptor (TCR) T cell therapy is a promising cancer treatment modality. However, its successful development for epithelial cancers may depend on the identification of high-avidity TCRs directed against tumor-restricted target antigens. The human papillomavirus (HPV) E7 antigen is an attractive therapeutic target that is constitutively expressed by HPV+ cancers but not by healthy tissues. It is unknown if genetically engineered TCR T cells that target E7 can mediate regression of HPV+ cancers. We identified an HPV-16 E7-specific, HLA-A*02:01-restricted TCR from a uterine cervix biopsy from a woman with cervical intraepithelial neoplasia. This TCR demonstrated high functional avidity, with CD8 coreceptor-independent tumor targeting. Human T cells transduced to express the TCR specifically recognized and killed HPV-16+ cervical and oropharyngeal cancer cell lines and mediated regression of established HPV-16+ human cervical cancer tumors in a mouse model. These findings support the therapeutic potential of this approach and established the basis for an E7 TCR gene therapy clinical trial in patients with metastatic HPV+ cancers (NCT02858310).

Novel genital alphapapillomaviruses in baboons (Papio hamadryas anubis) with cervical dysplasia.

Genital Alphapapillomavirus (αPV) infections are one of the most common sexually transmitted human infections worldwide. Women infected with the highly oncogenic genital human papillomavirus (HPV) types 16 and 18 are at high risk for development of cervical cancer. Related oncogenic αPVs exist in rhesus and cynomolgus macaques. Here the authors identified 3 novel genital αPV types (PhPV1, PhPV2, PhPV3) by PCR in cervical samples from 6 of 15 (40%) wild-caught female Kenyan olive baboons (Papio hamadryas anubis). Eleven baboons had koilocytes in the cervix and vagina. Three baboons had dysplastic proliferative changes consistent with cervical squamous intraepithelial neoplasia (CIN). In 2 baboons with PCR-confirmed PhPV1, 1 had moderate (CIN2, n = 1) and 1 had low-grade (CIN1, n = 1) dysplasia. In 2 baboons with PCR-confirmed PhPV2, 1 had low-grade (CIN1, n = 1) dysplasia and the other had only koilocytes. Two baboons with PCR-confirmed PhPV3 had koilocytes only. PhPV1 and PhPV2 were closely related to oncogenic macaque and human αPVs. These findings suggest that αPV-infected baboons may be useful animal models for the pathogenesis, treatment, and prophylaxis of genital αPV neoplasia. Additionally, this discovery suggests that genital αPVs with oncogenic potential may infect a wider spectrum of non-human primate species than previously thought.

Cervical and vaginal epithelial neoplasms in cynomolgus monkeys.

Papillomavirus-associated cervical cancer is the second most common neoplasm in women but has rarely been reported in animals. This report describes cervical and vaginal intraepithelial neoplasms identified in routine histologic specimens obtained from 20 (5.2%) of 385 female cynomolgus macaques (Macaca fascicularis) being used in long-term studies. Lesion incidence was similar in both control and hormonally treated animals (4.7% and 5.5%, respectively). Neoplasms included benign vaginal papillomas, mild to severe intraepithelial dysplasias, and two invasive cervical carcinomas. Common morphologic features included koilocytosis, nuclear atypia, and expansion of the basal epithelium. Selective staining of lesions with at least one of three papillomavirus antibodies was observed in all cases (20 of 20). In contrast, immunostaining of lesions was negative for Epstein-Barr-related virus proteins (0 of 20). The unique similarities between the observed lesions and those seen in women suggest that macaques may provide a suitable animal model for study of papillomavirus oncogenesis.

Dysplasia of the lower genital tract in the female monkey, Macaca fascicularis, the crab-eating macaque from Southeast Asia.

Seventy-eight female reproductive tracts from mature Macaca fascicularis caught in the wild were examined histologically for evidence of dysplasia in immature (metaplastic) and native (mature) squamous epithelium of the cervix and vagina. This series contained equal numbers of experimental animals and control and/or breeding colony animals. Five of 39 experimental animals showed dysplasia, whereas six animals with definite and two with questionable dysplasia were found in 39 control and breeding colony animals. On the basis of the foregoing facts, it would appear that these dysplastic lesions were of spontaneous origin and of undetermined etiology. Therefore, those investigators who experiment upon the reproductive tract of this species of monkey should be wary of interpreting any given experiment as "causing" dysplasia. Monkeys of this same species, born and reared in our Primate Center, have been examined for comparable dysplastic lesions of the lower female genital tract. None was found thus far but the study is continuing.