Lysis of Autologous Melanoma Cells by Tumor*Infiltrating Lymphocytes: Association With Clinical Response

Aebersold, Paul C.; Hyatt, Cornelia; Johnson, S; Hines, Ken; Korcak, L; Sanders, Melinda; Lotze, Michael T.; Topalian, Suzanne L.; Yang, James Chih‐Hsin; Rosenberg, Steven A.

doi:10.1093/jnci/83.13.932

Cited by 177 publications

(72 citation statements)

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“…Although functionally suppressed in vivo, cultured populations often are enriched with activated T cells and demonstrate cytotoxicity for autologous tumor cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Clinical trials involving the adoptive transfer of TIL supported with IL-2 have demonstrated regression of metastatic disease in a proportion of patients with renal cancer and melanoma (13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

Economou¹,

Belldegrun²,

Glaspy³

et al. 1996

J. Clin. Invest.

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Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and IL-2 appears to produce dramatic regressions in patients with metastatic melanoma and renal cancer. However, the in vivo mechanism of TIL function is not known. We conducted an UCLA Human Subject Protection Committee, Recombinant DNA Advisory Committee, and FDA-approved clinical trial using genetically-marked TIL to test the hypothesis that these cells have unique, tumorspecific in vivo trafficking patterns. TIL and PBL (as a control effector cell population) were isolated and expanded in parallel in vitro in IL-2-containing medium for 4-6 wk. During the expansion, TIL and PBL were separately transduced with the amphotropic retroviral vectors LNL6 and G1Na. Transduced TIL and PBL were coinfused into patients and their respective numbers measured in tumor, peripheral blood, and normal tissues; integrated provirus could be quantitated and distinguished by DNA PCR.Nine patients were treated (six melanoma, three renal) and received between 4.5 ϫ 10 8 and 1.24 ϫ 10 10 total cells. Both "marked" TIL and PBL could be detected circulating in the peripheral blood, in some patients for up to 99 d after infusion. Marked TIL and/or PBL could be detected in tumor biopsies in six of nine patients as early as day 6 and as late as day 99 after infusion. No convincing pattern of preferential trafficking of TIL vs. PBL to tumor was noted. Moreover, concurrent biopsies of muscle, fat, and skin demonstrated the presence of TIL/PBL in comparable or greater numbers than in tumor in five patients.The results of this double gene marking trial provide interesting insights into the life span and trafficking of adoptively transferred lymphocytes, but do not support the hypothesis that TIL specifically traffic to tumor deposits. ( J. Clin. Invest. 1996. 97:515-521.)

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Section: Introductionmentioning

confidence: 99%

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

Economou¹,

Belldegrun²,

Glaspy³

et al. 1996

J. Clin. Invest.

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“…On the other hand, two factors that were repeatedly reported to have a significant positive association to clinical response were short culture duration and telomere length (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients

Besser

Shapira‐Frommer

Treves

et al. 2010

Clinical Cancer Research

407

374

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Purpose: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability.Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients.The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.Experimental Design: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.Results: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.Conclusion: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer. Clin Cancer Res; 16(9); 2646-55. ©2010 AACR.

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“…TILs have been shown to be capable of specifically eliminating tumour cells (Aebersold et al, 1991), but also to be rendered potentially nonfunctional due to tumour-induced immunosuppression (Finke et al, 1990). In a previous study, we hypothesised that EMAP-II might act in such an immunosuppressive role, by directly inducing apoptosis in mitogen-activated lymphocytes (Murray et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer

et al. 2006

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Endothelial-monocyte-activating polypeptide-II (EMAP-II) is a novel multifunctional polypeptide with proinflammatory activity. We have previously shown that the recombinant and native forms of EMAP-II can induce apoptosis in mitogen-stimulated lymphocytes, and that the release of this protein into the extracellular milieu is enhanced by hypoxia. We hypothesised that hypoxia may lead to death of tumour-infiltrating lymphocytes (TILs) via an EMAP-II-dependent mechanism, thereby assisting tumours to evade the immune system. In this study, we used immunohistochemistry to detect EMAP-II, active caspase-3 and cleaved Poly (ADP-ribose) Polymerase (PARP) as indicators of apoptosis in TILs, and carbonic anhydrase IX (CA IX) as a surrogate marker of hypoxia. EMAP-II expression is associated with regions of hypoxia, and furthermore there is a significant association between TILs apoptosis and the presence of hypoxia. Using a coculture model of colorectal cancer cell/lymphocyte interactions, we were also able to demonstrate lymphocyte apoptosis induced by tumour cells, with concomitant caspase-3 activity. Lymphocyte killing was enhanced by direct cellcell contact, particularly by tumour cells exposed to hypoxic conditions. Our data support the hypothesis that hypoxia plays a role in immune evasion by tumour cells, through EMAP-II-dependent lymphocyte killing.

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Lysis of Autologous Melanoma Cells by Tumor*Infiltrating Lymphocytes: Association With Clinical Response

Cited by 177 publications

References 0 publications

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients

EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer

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