Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis

Abstract

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 À 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach.

Comprehensive single institute experience with melanoma TIL: Long term clinical results, toxicity profile, and prognostic factors of response

“…Symptoms of acute heart failure appeared before TIL infusion. To the best of our knowledge grade, 5 cardiac toxicity was not reported in any other TIL trial 12 …”

“…Another patient had late chemotherapy‐related fatal myelodysplastic syndrome 5 years after TIL ACT. Noteworthy, cardiac toxicity has not been reported in other TIL ACT trials 12 …”

“…Currently a phase 3 study is being conducted with TIL ACT in patients with metastatic melanoma (NCT02278887), and results of multiple phase 2 trials have been reported 7‐11 . A meta‐analysis of eight trials with altogether 332 patients has shown that Selected or Young TIL ACT in combination with high‐dose interleukin‐2 (IL‐2) administration can result in objective response rates of 43% (95% CI, 36%‐50%) in highly advanced, refractory patients with metastatic melanoma 12 …”

Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study

“…46 These findings underscore the hypothesis that patients who acquire immune escaped tumor variants after checkpoint blocking therapy may include modifications that also affect TIL-mediated tumor eradication, for example, antigen loss or HLA loss or other defects in the antigen processing pathway. 47 However, some of the patients in our study developing SD after ACT included a patient who initially had responded to anti-PD-1, indicating that secondary resistance to checkpoint therapy does not exclude patients to benefit from ACT therapy per se. This latter also applies to patients who develop (severe) autoimmune side effects leading to permanent discontinuation of checkpoint blockade, which occurs in approximately 15% of the cases.…”

Future Challenges in Cancer Resistance to Immunotherapy

“…One method to increase the number of tumor-reactive T cells is the adoptive transfer of ex vivo expanded tumor-infiltrating T cells (TILs) or transgenic T cells expressing a defined T cell receptor or chimeric antigen receptor (CAR T cells). The adoptive transfer of such cells has led to remarkable clinical responses, including the full regression of tumors [17][18][19]. Another therapeutic approach to increase the number of tumor-reactive T cells is the use of cancer vaccines.…”