Study of tumor-infiltrating lymphocytes for adoptive therapy of renal cell carcinoma (RCC) and metastatic melanoma: sequential proliferation of cytotoxic natural killer and noncytotoxic T cells in RCC.

K Hayakawa, M A Salmeron, D R Parkinson, A B Markowitz, A C von Eschenbach, S S Legha, C M Balch, M I Ross, L B Augustus, K Itoh
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引用次数: 25

Abstract

We investigated the immunological properties of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TIL), which were used for adoptive therapy of renal cell carcinoma (RCC) (seven patients) by focusing on natural killer (NK) cells, and metastatic melanoma (six patients) by focusing on cytotoxic T lymphocytes. TIL from five of seven cases proliferated well in culture with AIM-V serum-free medium and 1000 U/ml rIL-2 in 3-L gas permeable bags, whereas TIL from two RCCs exhibited delayed proliferation. Proliferation of CD3-CD56+ NK cells with major histocompatibility complex-nonrestricted cytotoxicity in RCC-TIL (n = 6, mean = 651-fold, ranging from 39- to 3450-fold) for the first 2-4 weeks was 63 times higher than that of noncytotoxic CD3+ T cells (n = 6, 10.3-fold ranging from 0.8 to 35-fold). Thereafter, CD3+ T cells predominantly proliferated, and proliferation of CD3+ T cells (n = 5, 743-fold) for 5-6 weeks were 24 times higher than that of CD3-CD56+ NK cells (n = 5, 31-fold). Significant numbers of RCC-TIL became adherent to the surfaces of the bags several weeks after initiation of culture. These adherent TIL consisted of more CD3-CD56+ NK cells and exhibited higher cytotoxicity than did nonadherent TIL. Adherent RCC-TIL produced interferon (IFN)-gamma, while nonadherent TIL did not. These results suggest that initially cytotoxic CD3-CD56+ NK cells and, later, noncytotoxic CD3+ T cells proliferated in culture of RCC-TIL for adoptive therapy. These noncytotoxic TIL were primarily transferred to RCC patients, who also received cyclophosphamide, IL-2, and IFN-alpha. In contrast to RCC-TIL, IL-2-activated melanoma TIL consisting of all CD3+ T cells displayed modest levels of cytotoxicity, primarily restricted to autologous melanoma cells in all cases tested. The cytotoxic melanoma TIL were adoptively transferred to melanoma patients. Three of seven RCC patients responded to the adoptive therapy.

肿瘤浸润淋巴细胞对肾细胞癌(RCC)和转移性黑色素瘤过继治疗的研究:细胞毒性自然杀伤细胞和非细胞毒性T细胞在肾细胞癌中的顺序增殖
我们研究了白细胞介素-2 (IL-2)激活的肿瘤浸润淋巴细胞(TIL)的免疫学特性,TIL通过聚焦自然杀伤(NK)细胞用于肾细胞癌(RCC)(7例)的过继治疗,通过聚焦细胞毒性T淋巴细胞用于转移性黑色素瘤(6例)的过继治疗。7例中有5例的TIL在AIM-V无血清培养基和1000 U/ml rIL-2在3-L透气袋中培养时增殖良好,而2例rcc的TIL增殖延迟。在RCC-TIL中,具有主要组织相容性复合物的CD3- cd56 + NK细胞(n = 6,平均= 651倍,范围为39- 3450倍)在前2-4周的增殖比无细胞毒性CD3+ T细胞(n = 6, 10.3倍,范围为0.8 - 35倍)高63倍。此后,CD3+ T细胞以增殖为主,5-6周CD3+ T细胞的增殖(n = 5,743倍)比CD3- cd56 + NK细胞的增殖(n = 5,31倍)高24倍。开始培养数周后,大量的RCC-TIL粘附在袋子表面。这些贴壁TIL由更多的CD3-CD56+ NK细胞组成,并表现出比非贴壁TIL更高的细胞毒性。粘附的RCC-TIL产生干扰素(IFN)- γ,而非粘附的TIL则没有。这些结果表明,最初的细胞毒性CD3- cd56 + NK细胞和后来的非细胞毒性CD3+ T细胞在RCC-TIL培养中增殖,用于过继治疗。这些非细胞毒性TIL主要转移到RCC患者,这些患者也接受了环磷酰胺,IL-2和ifn - α。与RCC-TIL相比,由所有CD3+ T细胞组成的il -2激活的黑色素瘤TIL显示出适度的细胞毒性,在所有测试病例中主要局限于自体黑色素瘤细胞。细胞毒性黑色素瘤TIL被移植到黑色素瘤患者。7名RCC患者中有3名对过继治疗有反应。
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