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Christian S. Hinrichs, M.D.
Cellular Therapy for Cancer
T-cell therapy can eradicate certain advanced malignancies, including melanoma and some B-cell malignancies. Application of this treatment modality is expanding as a result of genetic engineering that permits transfer of tumor specificity to any T cell through genes encoding tumor-specific receptors (T-cell receptors (TCR) or chimeric antigen receptors (CAR)). These genetically modified T cells can recognize tumors and 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 apply cellular therapies to cancers that express antigens that are expressed by tumors but not by healthy tissues. Human papillomavirus (HPV)-associated cancers--virally induced malignancies that constitutively express foreign oncoproteins--are prototypical of these cancers and the focus of our 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. Novel approaches for treating HPV-associated cancers are needed.
HPV-associated cancers are attractive targets for T-cell-based therapies due to their expression of the E6 and E7 oncoproteins. These viral antigens are expressed by cancers but not by healthy tissues, and they 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 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 4/8/2014.