Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as melanoma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins-SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.

Purpose Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer. Patients and Methods Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor-infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin. Results Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238). Conclusion Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted.

Purpose: Tumor-infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunologic impact of unscreened, CD8þ enriched "young" TIL.Experimental Design: Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8þ enriched young TIL and IL-2 following nonmyeloablative lymphodepletion (NMA). Twentythree additional patients were treated with CD8þ enriched young TIL and IL-2 after lymphodepletion with NMA and 6 Gy of total body irradiation.Results: Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8þ enriched young TIL and NMA had an objective response (Response Evaluation Criteria in Solid Tumors) including 3 complete responders. Eleven of 23 patients (48%) treated with TIL and 6 Gy total body irradiation had an objective response including 2 complete responders. At 1 month after TIL infusion the absolute CD8þ cell numbers in the periphery were highly correlated with response.Conclusions: This study shows that a rapid and simplified method can be used to reliably generate CD8þ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients. Clin Cancer Res; 16(24); 6122-31. Ó2010 AACR.Patients with metastatic melanoma have limited treatment options, and only 2 of these treatments have received Food and Drug Administration approval. Interleukin (IL)-2 can mediate durable complete responses in 3% to 5% of treated patients, with an overall response rate of about 13% to 16% (1); decarbazine results in a 15% response rate with rare durable responses (2). Other promising experimental treatments being evaluated in randomized trials for efficacy and toxicity include inhibitors of the dominant BRAF V600E mutation (3) and an anti-CTLA-4 antibody (4, 5). Despite these recent advances, a pressing need remains for effective treatments.Adoptive cell therapy (ACT) combines lymphodepletion with a patient's own tumor reactive tumor-infiltrating lymphocytes (TIL) to generate an individualized therapy (6). A total of 93 refractory melanoma patients were treated at our institution with TIL selected for tumor recognition following 1 of 3 different lymphodepleting regimens (7). Forty-three patients received nonmyeloablative chemotherapy (NMA) alone, 25 patients received NMA with 2 Gy of total body irradiation (TBI), and 25 patients received NMA plus 12 Gy TBI. The objective response rates [Response Evaluation Criteria in Solid Tumors (RECIST)] for t...