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Christian S. Hinrichs, M.D.
Cellular Therapy for Cancer
T cell therapy can eradicate certain advanced malignancies, including melanoma and Epstein-Barr virus (EBV)-associated cancers. Application of this treatment modality is expanding as a result of advances in genetic engineering that permit transfer of tumor specificity to any T cell through genes encoding tumor-specific T antigen receptors (T cell receptors (TCR) or chimeric antigen receptors (CAR)). These genetically modified cells can recognize tumors and can mediate cancer regression in patients. Targeting of shared tumor/self antigens with this strategy can induce tumor responses but has been limited by autoimmune toxicities. We are working to extend cellular therapies to cancers that express antigens that are expressed by tumors but not by normal tissues. Human papillomavirus (HPV)-associated cancers--virally induced malignancies that constitutively express foreign oncoproteins--are prototypical for these cancers and the focus of our present efforts.
HPV-associated cancers occur at varied sites including the uterine cervix, oropharynx, anus, vagina, vulva, and penis. Metastatic disease from these malignancies is incurable, and durable palliation is rarely achieved with systemic therapies. Clinical trials with novel chemotherapeutic and targeted agents have resulted in only modest gains. Vaccines can prevent HPV infection, but uptake has been less than hoped, and these vaccines do not treat established cancers. Thus, novel approaches for treating HPV-associated cancers are needed.
HPV-associated cancers are rational targets for T-cell-based therapies due to their expression of the E6 and E7 oncoproteins. These viral antigens induce malignant transformation and are constitutively expressed by cancers but not by healthy tissues. They also contribute to the proliferation and survival of cancer cells. Thus, they are ideal therapeutic targets--tumor specific and functionally important.
We are pursuing two T-cell-based approaches to targeting these antigens. The first is adoptive cell transfer therapy with tumor infiltrating lymphocytes (TIL). TIL therapy involves the surgical resection of a patient's tumor, followed by the expansion of the T cells from the tumor to massive numbers, and then the reinfusion of the T cells back into the patient. This approach has resulted in complete and durable responses in metastatic melanoma. TIL can be generated from HPV-associated cancers and these TIL can have reactivity against the HPV E6 and E7 oncoproteins. A clinical trial (A Phase II Study of Lymphodepletion Followed by Autologous Tumor-Infiltrating Lymphocytes and High-Dose Aldesleukin for HPV-Associated Cancers) is presently underway to test the efficacy of TIL therapy for metastatic HPV-associated cancers.
The second T-cell-based approach that we are studying uses T-cell receptor (TCR)-gene engineered T cells. This strategy exploits gene transfer technology to confer tumor reactivity--via genes encoding tumor reactive TCRs--to T cells from the peripheral blood of patients. We are isolating T cells that recognize the HPV oncoproteins and the genes for the TCRs that mediate this recognition from HPV-positive cancer TIL. With these genes we are engineering T cells to have reactivity against the HPV oncoproteins and HPV-positive tumors to create the next generation of cellular therapies.
This page was last updated on 11/20/2013.