Adoptive T-cell Therapy Promising for Metastatic Cervical Cancer
Complete regression metastatic cervical cancer in a woman treated with a single infusion of HPV-targeted tumor-infiltrating lymphocytes. The yellow arrows point to tumors.
Over 4,000 women in the U.S. die from cervical cancer each year. Nearly all cases of the disease are caused by infection with human papilloma viruses (HPVs), particularly strains 16 and 18. Cervical cancer can be prevented with vaccination against HPVs before the initiation of sexual activity and can be detected early with regular screening via the Pap test and/or HPV DNA testing. If the disease progresses to a metastatic state, however, it is generally incurable and difficult to treat with chemotherapy.
Adoptive T-cell therapy (ACT) is a form of immunotherapy in which T cells taken from a patient are grown in culture and infused back to the patient for the treatment of cancer. Those T cells that react to particular tumor antigens may recognize and eliminate tumor cells. ACT has not been studied extensively in epithelial cancers but has resulted in complete responses in some patients with B-cell malignancies and malignant melanoma. Christian Hinrichs, M.D., of CCR’s Surgery Branch, and his colleagues designed a clinical trial to study whether cancer-derived T cells that react to HPV-16 or HPV-18 E6 and E7 oncoproteins, so called HPV-TILs, could stimulate tumor regression in women with metastatic cervical cancer.
The researchers treated nine women, ranging in age from 30 to 59 years (median, 37 years). Four had squamous cell carcinomas, three had adenocarcinomas, and two had adenosquamous carcinomas. Only two patients’ tumors were predominantly infected with HPV-16; in the rest, HPV-18 was the leading type. All of the women had multiple metastases and had been treated previously with platinum chemotherapy, six of whom received combination chemotherapy regimens.
The investigators gave the trial participants a white blood cell-depleting chemotherapy regimen followed by a single infusion of HPV-TILs and one or more doses of aldesleukin, which increases the growth and activity of white blood cells, including T cells. Doses of the HPV-TILs ranged from 33 to 152 x 109 cells (median, 80 x 109) and incorporated both CD4+ and CD8+ T cells. Encouragingly, three of the women achieved objective tumor responses. Two participants, one with HPV-16-positive squamous cell carcinoma and one with HPV-18-positive adenocarcinoma, experienced complete regressions of their tumors that were ongoing 22 and 15 months after treatment, respectively. The third woman had a partial response that lasted three months.
None of the patients exhibited acute toxicities from HPV-TIL infusion or autoimmune adverse events. The most common toxicities were hematologic and were an expected effect of the white blood cell-depleting regimen. No participant experienced severe cytokine release syndrome, but the two patients with complete responses did have transiently elevated cytokine levels that were associated with fevers.
The researchers then examined the frequency of HPV-reactive T cells in the infused HPV-TILs using interferon-gamma (IFN-γ) enzyme-linked immunospot, CD137 upregulation, and INF-γ production assays. They found that the three patients treated with the most HPV-reactive cells were those who experienced objective tumor responses. Conversely, two patients whose infused cells had no HPV reactivity by any of the assays demonstrated no clinical responses. Thus, HPV reactivity was positively associated with tumor response, but the results are limited by the small sample size of the trial.
The scientists also studied patient peripheral blood samples one month after HPV-TIL infusion to determine whether the infusion increased the frequency of HPV-reactive T cells. In fact, six of the participants’ cells showed increased reactivity to E6 and E7 one month after treatment. The three patients with the highest frequency of HPV-reactive peripheral blood cells also had objective tumor responses. These results suggest a correlation between clinical response and the repopulation of patients’ peripheral blood with HPV-reactive T cells, but additional patients will need to be studied to confirm this observation.
Finally, the investigators analyzed the peripheral blood of the three patients with objective clinical responses at later time points. T cells from all three demonstrated elevated HPV reactivity at two, 11, and 13 months after treatment, respectively. The oncoprotein targeted by the peripheral T cells agreed with that targeted by the infused cells, suggesting that responding patients experienced prolonged repopulation of infused T cells that react to HPV.
The results of this first clinical trial of ACT as a treatment for patients with metastatic cervical cancer showed that complete regression is possible after one dose of HPV-TILs. The HPV reactivity of the infused cells and their ability to repopulate the peripheral blood may dictate clinical response. Additional studies of HPV-TILs in cervical cancer and other HPV-related diseases are warranted.Summary Posted: 04/2015
Stevanovic S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, Dudley ME, Yang JC, Sherry RM, Kammula US, Restifo NP, Rosenberg SA, Hinrichs CS. Complete Regression of Metastatic Cervical Cancer after Treatment with Human Papillomavirus-Targeted Tumor-Infiltrating T cells. JCO. March 30, 2015 PubMed Link