Shugo Ueda

Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer

Purpose: Preparative lymphodepletion, the temporal ablation of the immune system, has been reported to promote persistence of transferred cells along with increased rates of tumor regression in patients treated with adoptive T-cell therapy. However, it remains unclear whether lymphodepletion is indispensable for immunotherapy with T-cell receptor (TCR) gene–engineered T cells. Experimental Design: We conducted a first-in-man clinical trial of TCR gene-transduced T-cell transfer in patients with recurrent MAGE-A4–expressing esophageal cancer. The patients were given sequential MAGE-A4 peptide vaccinations. The regimen included neither lymphocyte-depleting conditioning nor administration of IL2. Ten patients, divided into 3 dose cohorts, received T-cell transfer. Results: TCR-transduced cells were detected in the peripheral blood for 1 month at levels proportional to the dose administered, and in 5 patients they persisted for more than 5 months. The persisting cells maintained ex vivo antigen-specific tumor reactivity. Despite the long persistence of the transferred T cells, 7 patients exhibited tumor progression within 2 months after the treatment. Three patients who had minimal tumor lesions at baseline survived for more than 27 months. Conclusions: These results suggest that TCR-engineered T cells created by relatively short-duration in vitro culture of polyclonal lymphocytes in peripheral blood retained the capacity to survive in a host. The discordance between T-cell survival and tumor regression suggests that multiple mechanisms underlie the benefits of preparative lymphodepletion in adoptive T-cell therapy. Clin Cancer Res; 21(10); 2268–77. ©2015 AACR.

Overcoming regulatory T‐cell suppression by a lyophilized preparation of Streptococcus pyogenes

Cancer vaccines have yet to yield clinical benefit, despite the measurable induction of humoral and cellular immune responses. As immunosuppression by CD4+CD25+ regulatory T (Treg) cells has been linked to the failure of cancer immunotherapy, blocking suppression is therefore critical for successful clinical strategies. Here, we addressed whether a lyophilized preparation of Streptococcus pyogenes (OK‐432), which stimulates Toll‐like receptors, could overcome Treg‐cell suppression of CD4+ T‐cell responses in vitro and in vivo. OK‐432 significantly enhanced in vitro proliferation of CD4+ effector T cells by blocking Treg‐cell suppression and this blocking effect depended on IL‐12 derived from antigen‐presenting cells. Direct administration of OK‐432 into tumor‐associated exudate fluids resulted in a reduction of the frequency and suppressive function of CD4+CD25+Foxp3+ Treg cells. Furthermore, when OK‐432 was used as an adjuvant of vaccination with HER2 and NY‐ESO‐1 for esophageal cancer patients, NY‐ESO‐1–specific CD4+ T‐cell precursors were activated, and NY‐ESO‐1–specific CD4+ T cells were detected within the effector/memory T‐cell population. CD4+ T‐cell clones from these patients had high‐affinity TCRs and recognized naturally processed NY‐ESO‐1 protein presented by dendritic cells. OK‐432 therefore inhibits Treg‐cell function and contributes to the activation of high‐avidity tumor antigen‐specific naive T‐cell precursors.

Multicenter phase II study of triplet combination chemotherapy with paclitaxel, cisplatin, and S-1 for advanced gastric cancer (OGSG 0703).

124 Background: Docetaxel combined with cisplatin and 5-fluorouracil is active in advanced gastric cancer, but not generally accepted because of its substantial toxicities. We conducted a multicenter phase II study of triplet combination using paclitaxel, cisplatin and S-1 (PCS) as first-line treatment for advanced gastric cancer. METHODS Patients with previously untreated, locally advanced or metastatic measurable gastric cancer, a performance status < 2, age of 20-75 years, and adequate organ functions were given intravenous paclitaxel at 70 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 15, plus oral S-1 at 40 mg/m2 b.i.d. on days 1 to 21, followed by 2-week rest, repeated every 5 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient refused the therapy. Study endpoints included overall response rate (ORR) as primary, progression free survival (PFS), overall survival (OS), and toxicity. Sample size of 40 patients was determined to reject the ORR of 55% under the expectation of 75% with a power of 80% and a one-sided α of 5%. RESULTS A total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. ORR was 46.9% (95% CI: 32.5-61.7%). The median PFS and median OS were 5.4 months (95% CI: 4.1-7.0) and 11.5 months (95% CI: 7.3-16.1), respectively. Frequent grade 3/4 toxicities were neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), diarrhea (8%) and fatigue (8%). There was no treatment-related death. CONCLUSIONS Triplet combination chemotherapy with PCS demonstrated superior feasibility with promising antitumor activity, though which did not meet the statistical hypothesis, for advanced gastric cancer.

Multicenter phase II study of combination therapy with paclitaxel, cisplatin, and S-1 for adavanced gastric cancer (OGSG0703).

e14654 Background: A multicenter phaseII study was conducted to evaluate the efficacy and safety of a combination regimen (PCS) with paclitaxel, cisplatin, and S-1 in patients with advanced gastric cancer in an outpatient setting. METHODS Patients with previously untreated metastatic or recurrent gastric cancer received intravenous paclitaxel at 70 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 15, plus oral S-1 at 40 mg/m2 b.i.d. on days 1 to 21,followed by 2 weeks off, in a 35-day cycle. RESULTS A total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. The overall response rate was 46.9% (95% CI: 32.5-61.7%). The median progression-free survival and median overall survival were 5.4 months (95% CI:4.1-7.0) and 11.5 months (95% CI:7.3-16.1), respectively. Frequent grade 3/4 toxic effects included neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), and fatigue (10%). There was no treatment-related death. CONCLUSIONS In this study, the predicted response rate was not achieved employing this combination regimen with paclitaxel, cisplatin, and S-1, although it was found to be well- tolerated.