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

Abstract

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).

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

“…Each of the TCR pairing strategies listed above need not be used in isolation. Indeed, a TCR construct which incorporates all three classes of modifications (murinization, additional cysteine residue, TM hydrophobicity) has recently entered a first in human clinical trial (NCT02858310) . While in principle concerns regarding TCR chain mispairing may be mitigated by condensing the structure of the TCR heterodimer into a scTCR format, no scTCR constructs have been clinically tested.…”

“…Detailed analyses from both trials revealed that the affinity‐enhanced TCRs exhibited unanticipated cross‐reactivity to antigens expressed in critical normal tissues . Consequently, testing for potential cross‐reactivity is now routinely performed during the pre‐clinical development of novel TCRs . It is important to note, however, that development of off‐tumor/off‐target toxicities is by no means a universal property of all affinity‐enhanced TCRs.…”

“…In the case of HPV, the E6 and E7 oncoproteins are constitutively expressed and clonally maintained within patients . Two HLA‐A2‐restricted TCRs specific for epitopes derived from the HPV‐16 E6 and E7 oncoproteins have entered first in human clinical trials (NCT02280811 and NCT02858310). Preliminary results suggest that both TCRs are active and capable of inducing objective responses in patients with HPV‐associated cervical, anal, and head and neck cancers.…”

“…127,130,131 Consequently, testing for potential cross-reactivity is now routinely performed during the pre-clinical development of novel TCRs. 123,[132][133][134] It is important to note, however, that development of off-tumor/off-target toxicities is by no means a universal property of all affinity-enhanced TCRs. Indeed, an affinity-enhanced anti-NY-ESO-1 TCR has demonstrated exceptional anti-tumor efficacy in multiple clinical trials without evidence of off-target toxicities.…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Incorporation of hydrophobic residues at evolutionary-permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity [66]. Since then, this approach was successfully applied to a number of TCRs [8,[67][68][69][70].…”