Adoptive Cell Therapy with Tumor Infiltrating Lymphocytes and Intermediate Dose Interleukin-2 for Metastatic Melanoma

138 Background: Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can produce long lasting treatment responses in patients (pts) with metastatic melanoma. In our initial report of 31 treated pts, we demonstrated overall response rate (ORR) of 48%. Due to the evolution of treatment options for metastatic melanoma with heavy reliance on immunomodulatory therapies, we sought to re-evaluate responses in the era of checkpoint blockade. Methods: Pts receive treatment consisting of 7 days of lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. High dose interleukin-2 (720,000 IU/kg IV q 8 hrs up to 15 doses) was infused after TIL infusion. Responses were assessed by imaging per irRC. Results: A total of 74 pts have been treated in our initial TIL study with an updated ORR assessment of 43%. Stratification of pts according to their checkpoint blockade immune-modulator therapy prior to TIL ACT, demonstrated that prior Ipilimumab (Ipi) decreased ORR to 33% compared to 51% in checkpoint naïve pts and decreased overall survival (OS) post-TIL therapy (median 7.7 vs 24.6 months respectively). There were too few pts to assess the impact of anti-PD1 as a single agent. A multiparametric analysis revealed that LDH levels at the time of therapy mainly influences OS and ORR to TIL but still could not invalidate the impact of Ipi prior to TIL ACT. The durability of the response was also found to be different between the 2 groups (30% for Ipi prior and 50% No Ipi prior). This new reality also impacted previously reported parameters that correlated with ORR to TIL ACT such as the expression of B-and-T lymphocyte attenuator (BTLA) on CD8+ TIL. Interestingly, assessment of mutation load (ML) of the tumors prior to TIL ACT showed that the check point naïve group display a high ML ( > 100) within their tumor whereas some patients who had Ipi prior to TIL have a low ML ( < 100). Conclusions: Our preliminary analysis shows that pre-treatment with Ipi decreases ORR to TIL ACT. Understanding how prior ipi modifies TIL, the tumor and microenvironment will help to define the full extent of the impact and how to best treat Ipi refractory pts with TIL. Clinical trial information: NCT00338377.

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Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma

World Journal of Surgical Oncology ◽

10.1186/1477-7819-10-113 ◽

2012 ◽

Vol 10 (1) ◽

pp. 113 ◽

Cited By ~ 8

Author(s):

Melissa M Alvarez-Downing ◽

Suzanne M Inchauste ◽

Mark E Dudley ◽

Donald E White ◽

John R Wunderlich ◽

...

Keyword(s):

Liver Resection ◽

Cell Therapy ◽

Minimally Invasive ◽

Metastatic Melanoma ◽

Adoptive Cell Therapy ◽

Tumor Infiltrating Lymphocytes ◽

Minimally Invasive Liver Resection ◽

Infiltrating Lymphocytes

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Randomized Selection Design Trial Evaluating CD8+-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2012.46.6441 ◽

2013 ◽

Vol 31 (17) ◽

pp. 2152-2159 ◽

Cited By ~ 135

Author(s):

Mark E. Dudley ◽

Colin A. Gross ◽

Robert P.T. Somerville ◽

Young Hong ◽

Nicholas P. Schaub ◽

...

Keyword(s):

Cell Therapy ◽

Adoptive Cell Therapy ◽

Interleukin 2 ◽

Evaluation Criteria ◽

Tumor Infiltrating Lymphocytes ◽

Peripheral Blood Lymphocytes ◽

Response To Treatment ◽

High Dose ◽

Autologous Tumor ◽

Infiltrating Lymphocytes

Purpose Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8+-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8+-enriched TILs responded. Conclusion A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8+-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

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Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients

Journal of Immunology Research ◽

10.1155/2018/3530148 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Mélanie Saint-Jean ◽

Anne-Chantal Knol ◽

Christelle Volteau ◽

Gaëlle Quéreux ◽

Lucie Peuvrel ◽

...

Keyword(s):

Cell Therapy ◽

Adoptive Cell Therapy ◽

Interleukin 2 ◽

Tumor Infiltrating Lymphocytes ◽

Advanced Melanoma ◽

Autologous Tumor ◽

Unresectable Stage ◽

Melanoma Patients ◽

Infiltrating Lymphocytes

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n=4) or IV (n=6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

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