Adoptive cell transfer (ACT) can mediate durable regression in patients with metastatic melanoma, and some patients with initial response may progress, requiring salvage therapy. We report updated follow-up on a retrospective review of patients with metastatic melanoma receiving ACT at a single institution from 2000 to 2022. We identified patients with objective response (RECIST 1.0) or stable disease for at least 6 months (SD6) before experiencing oligoprogression in up to three extracranial sites managed with surgery. The primary outcomes were progression-free survival (PFS) and overall survival (OS) after surgery. We also performed an exploratory analysis for genomic mechanisms of tumor escape. In total, 138 patients with metastatic melanoma treated with ACT had an objective response or SD6 before experiencing disease progression. Of these, 30 (21

Adoptive cell therapy with tumor infiltrating lymphocytes is FDA approved for metastatic melanoma. TIL from patients with melanoma and factors relating to growth and reactivity have been studied; however, this has not been explored in patients with epithelial cancers. Metastatic epithelial tumors resected for TIL growth from 2014 to 2023 were analyzed. Two hundred and ninety-one operations were performed to collect TIL for potential treatment. Of these, 263 harvests were each processed for up to 24 individual fragment cultures and screened for neoantigen recognition of the expressed products of cancer mutations. Patient and tumor characteristics were collected. Endpoints were growth (defined as more than half of all fragment cultures expanded for viable cryopreservation) and patient-specific neoantigen reactivity (release of interferon-γ in cocultures measured by ELISpot and 4-1BB upregulation on flow cytometry). TIL fragments reached adequate growth for screening by 21 days. Metastatic resections from lung were more likely to grow TIL than all other resection sites combined (95

PURPOSE:Acral lentiginous melanoma is a subtype of cutaneous melanoma arising from palmar, plantar, or subungual skin. These tumors are characterized by aggressive biology, a low tumor mutational burden (TMB), and diminished sensitivity to immune checkpoint blockade. It is unknown whether adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TIL) has efficacy in patients with acral melanoma. METHODS:We analyzed prospectively collected data from 442 patients with metastatic cutaneous melanoma who were treated on clinical trials of ACT-TIL at a single institution between 1999 and 2018. Although blinded to treatment outcome and genomic data, we retrospectively identified patients who had acral subtype on the basis of clinicopathologic data available at the time of diagnosis. We then evaluated the ACT-TIL treatment outcomes of patients with acral melanoma and compared them with contemporaneously treated patients with nonacral melanoma. RESULTS:Out of 442 included patients, 30 (7%) had acral melanoma while 412 (93%) had nonacral melanoma. Cohorts had similar clinical characteristics, protocol enrollment, and treatment-related factors. The objective response rate to ACT-TIL in patients with acral and nonacral melanomas was 43% and 40%, respectively (P = .87), with 3% and 16% having complete responses (CRs; P = .07). Median progression-free survival was 3.5 and 4.1 months (P = .40) and median overall survival was 13 and 17 months (P = .79), respectively. Acral melanomas had lower TMB and ultraviolet mutational signature scores than nonacral melanomas. CONCLUSION:ACT-TIL can mediate objective responses in patients with metastatic acral melanoma, and outcomes in patients with acral disease were unexpectedly comparable with those of contemporaneously treated patients with nonacral cutaneous melanoma. Further research is necessary to understand the immunologic basis of responses to ACT-TIL in acral melanoma and to increase the frequency of CRs.

PDF file - 73K, MDA and MHC II expression demonstrates a site cluster-specific pattern. (A) The distribution of antigen expression for each anatomic site cluster. The p-values indicate the probability that no variability exists across the site clusters as determined by the Kruskal-Wallis test.

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

Table S1 describes patient characteristics by clinical response to treatment

Post ACT survival (MSS and PFS) data for patients with BRAF V600E/K (+) tumors with respect to prior therapy

PDF file - 51K, Pairwise comparison of antigen expression by individual anatomic site cluster. Shown are p value results of Cochran-Armitage test for trend. p <0.005 considered significant (bold, underlined), p <0.05-0.005 considered a trend (bold).

PDF file - 65K, TYR expression varies with the degree of CD8+ and CD4+ T cell infiltrate. (A) The distribution of antigen expression for given CD8 (blue) infiltrate score (0-3+, column). (B) The distribution of antigen expression for given CD4 (green) infiltrate score (0-3+, column).

Table S3 describes treatment-related adverse events

PDF file - 47K, Individual dendrogram distance matrices for the melanoma differentiation antigens. Dendrogram distant matrices calculated from DendroUPGMA.

CCR Translation for This Article from CTLA-4 Blockade with Ipilimumab: Long-term Follow-up of 177 Patients with Metastatic Melanoma

Table S2 describes treatment characteristics by clinical response to treatment

PDF file - 57K, Pairwise comparison of antigen expression by individual anatomic site. Shown are p value results of Cochran-Armitage test for trend. p <0.005 considered significant (bold, underlined), p <0.05-0.005 considered a trend (bold).

PDF file - 50K, Dendrogram distance matrix for all melanoma differentiation antigens. Dendrogram distant matrix calculated from DendroUPGMA.

A CONSORT diagram of patients on trials not previously reported

Supplementary Figure S1; Supplementary Table S1.

Abstract Purpose: Adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can mediate durable responses in patients with metastatic melanoma. This retrospective analysis provides long-term follow-up and describes the effect of prior therapy on outcomes after ACT-TIL. Patients and Methods: Patients with metastatic melanoma underwent surgical resection of a tumor for generation of TILs and were treated with a lymphodepleting preparative regimen followed by adoptive transfer of TILs and intravenous IL2. Clinical characteristics of enrolled patients and treatment characteristics of TIL infusion products over two decades of ACT were analyzed to identify predictors of objective response. Results: Adoptive transfer of TILs mediated an objective response rate of 56% (108/192) and median melanoma-specific survival of 28.5 months in patients naïve to anti–programmed cell death-1 (PD-1) therapy compared with 24% (8/34) and 11.6 months in patients refractory to anti–PD-1 (aPD-1). Among patients with BRAF V600E/K–mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs. 60%) and decreased survival (9.3 vs. 50.7 months) when compared with those patients naïve to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the aPD-1–naïve cohort have ongoing responses after a single treatment and 10-year melanoma-specific survival of 96%. Conclusions: Patients previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma. See related commentary by Sznol, p. 5156

Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall survival were analyzed. Among 144 total patients, 15 patients with treated and 18 patients with untreated brain metastases were identified. Intracranial objective responses (OR) occurred in 28% patients with untreated brain metastases. The systemic OR rates for patients with M1c disease without identified brain disease, treated brain disease, and untreated brain disease, and were 49%, 33% and 33%, respectively, of which 59%, 20% and 16% were durable at last follow-up. The site of untreated brain disease was the most likely site of initial tumor progression (61%) in patients with untreated brain metastases. Overall, we found that ACT with TIL can eliminate small melanoma brain metastases. However, following TIL therapy these patients frequently progress in the brain at a site of untreated brain disease. Patients with treated or untreated brain disease are less likely to achieve durable systemic ORs following TIL therapy compared with M1c disease and no history of brain disease. Melanoma brain metastases likely require local therapy despite the systemic effect of ACT.