Abstract
ObjectivesTo test the antitumor potential of lymphocytes transferred via adoptive cell therapy (ACT) in a mouse model of human gastric cancer (GC), and to evaluate the clinical efficacy and safety of combining lymphocytes as adjuvant therapy with first-line chemotherapy in patients with GC. MethodsWe constructed a human GC xenograft model in sublethally irradiated 6-8-week-old male NCG mice. MKN-45 cells (1 × 106 cells/mouse) were subcutaneously injected into mice's flanks. After tumors had become palpable, we randomized the mice into control, ACTIL-2, and ACTIL-15 groups. Human lymphocytes were then injected into mouse tail veins. In addition, 63 human patients with histologically or cytologically confirmed stage III-IV GC randomly received S-1 + oxaliplatin + ACTIL-15 (combination therapy group) or S-1 + oxaliplatin (chemotherapy group). ResultsIn the mouse study, treatment with ACTIL-15 cells inhibited tumor growth on adoptive transfer, and mice that received ACTIL-15 cells had significantly longer survival rates (p < 0.05, ACTIL-15 vs. ACTIL-2). In the human study, the median survival rate of patients in the combination therapy group was 472days (95% confidence interval [CI], 276-668days), whereas that of patients in the chemotherapy group was 266days (95% CI, 200-332days; p < 0.05). Eleven percent (7/63) of patients had adverse reactions, but these reactions did not interfere with treatment. ConclusionAdoptive transfer of ACTIL-15 cells in a mouse model of GC and in patients with advanced GC treated with S1 + oxaliplatin improved survival rates in both, with an acceptable safety profile.
Highlights
Gastric cancer is challenging to treat, with few patients eligible for extensive surgery and a median survival of 3–5 months for those with an unresectable disease[1]
Expression of the activation antigen CD25 on CD3+CD56- or CD3+CD56+ T lymphocytes cultured with IL-15 was significantly higher than with IL-2 (Figure 1B)
We considered that ACTIL-15 cells might have differential effects in vivo and in vitro and, may be effective against MKN-45 cells in vivo
Summary
Gastric cancer is challenging to treat, with few patients eligible for extensive surgery and a median survival of 3–5 months for those with an unresectable disease[1]. Clinical trials with various treatment regimens have produced improved results, but the median survival is still less than one year[2,3,4,5]. No standard third-line therapy is available for patients with advanced gastric cancer who have not responded to two or more lines of chemotherapy. The standard of care for the first-line treatment of unresectable advanced or metastatic gastric/gastroesophageal junction cancer is oral fluoropyrimidine (e.g., capecitabine or S-1) or capecitabine plus cisplatin or oxaliplatin[8,9,10]. Oxaliplatin can induce immunological death of tumor cells and enhance the efficacy of immunologic agents[13]
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