Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study

Chandran, Smita S.; Somerville, Robert; Yang, James Chih‐Hsin; Sherry, Richard M.; Klebanoff, Christopher A.; Goff, Stephanie L.; Wunderlich, John R.; Danforth, David N.; Zlott, Daniel; Paria, Biman C.; Sabesan, Arvind; Srivastava, Abhishek K.; Xi, Liqiang; Pham, Trinh; Raffeld, Mark; White, Donald E.; Toomey, Mary Ann; Rosenberg, Steven A.; Kammula, Udai S.

doi:10.1016/s1470-2045(17)30251-6

Cited by 238 publications

(197 citation statements)

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“…However, a lack of PD-L1 expression does not mean that uveal melanoma is 'immunotherapy resistant'. Indeed, immunotherapeutic interventions like adoptive T-cell transfer seems promising for control of metastatic disease in uveal melanoma [43]. Our study is limited by the number of samples assessed for PD-1 expression on TILs as well as the lack of characterization of TILs to identify specific lymphocyte subsets.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

et al. 2017

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Aim:To compare PD-L1 expression between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). Materials & methods: A total of 295 MCM and 78 MUM specimens were analyzed for tumor cell PD-L1 expression. Additionally, 91 MCM and 45 MUM specimens were analyzed for PD-1 expression on tumor-infiltrating lymphocytes. Results: A total of 77/295 (26.1%) MCM specimens expressed PD-L1 as compared to 4/78 (5.1%) MUM specimens (p < 0.0001). PD-1 expression on tumor-infiltrating lymphocytes was greater in MCM (73.6%; 67/91) than in MUM (51.1%; 23/45), respectively (p = 0.009). Conclusion: Significant differences exist in PD-L1 expression between MCM and MUM. The lower PD-L1 expression in MUM may provide a rationale for failure of PD-1 inhibitor therapy and suggests that immune evasion in this disease may occur via alternative mechanisms. Uveal melanoma originates from melanocytes in the choroid, ciliary body and iris of the eye [1]. It is the most common primary intraocular malignancy in adults and occurs almost exclusively in Caucasians, with an incidence of approximately 5-7/million/year in certain European populations [2]. In the USA, it represents about 5% of all melanoma diagnoses [1,3]. Uveal melanoma tends to recur in approximately 50% of the cases despite successful therapy of the primary tumor, in particular those whose tumors have certain risk factors for metastasis, such as large tumor size, ciliary body location, epithelioid cell morphology, high mitotic count and chromosomal abnormalities (e.g., chromosome 3 loss, 8q gain) [4]. Compared with cutaneous melanoma, uveal melanoma is characterized by its distinct genetic profile and clinical presentation, where most metastases are detected in the liver [5][6][7][8][9][10]. Once uveal melanoma metastasizes, prognosis is poor because metastatic uveal melanoma (MUM) tends to be widespread within the liver and only surgically resectable in some cases [11,12]. Therefore, there is an unmet need for investigating effective systemic therapies.Systemic immunotherapy with checkpoint inhibitors has vastly improved the treatment of metastatic cutaneous melanoma (MCM), leading to long-term durable responses [13,14]. MUM patients are often treated with immune checkpoint inhibitors identical to those used in the treatment of MCM (anti-programmed death-1 [PD-1] and anti-CTLA4 [Cytotoxic T-lymphocyte-associated protein 4] antibodies), either as monotherapy or in combination. Contrary to MCM, MUM demonstrates a poor response to these immune checkpoint blockades [15] (Table 1) [16][17][18][19][20][21][22][23] One of the mechanisms by which tumors evade the immune system is through upregulation and expression of PD-L1 protein on their surface. PD-L1 on tumor cells interacts with PD-1 receptor expressed on activated T cells, leading to T-cell exhaustion, anergy and ultimately, immune response abandonment [24,25]. Inhibition of the PD-1/PD-L1 interaction is the mechanism by which anti-PD-1 antibodies induce T-cell activation and antitumor effect.We evaluated the express...

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Section: Discussionmentioning

confidence: 99%

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

et al. 2017

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“…No significant difference was seen among responders and non-responders in terms of mutation burden in tumors. On the other hand, TIL products with either less than 3% tumorreactive T cells, less than 2 × 10 9 tumor-reactive T cells, or less than 100 pg/mL of tumor-induced IFN-γ release yielded poor clinical responses [65] . This study indicated that adoptive transfer of autologous TILs can mediate objective tumor regression in patients with metastatic UM.…”

Section: Adoptive Immunotherapy Using Tumor-infiltrating T Cellsmentioning

confidence: 98%

“…In a study at National Cancer Institute (NCT01814046), 21 metastatic UM patients who were HLA-A2 positive were treated with TIL therapy in phase II clinical trial [65,66] . Seven of 20 evaluable patients showed objective tumor regression including 6 patients with PR and one patient with CR, ongoing at 21 months post therapy.…”

Section: Adoptive Immunotherapy Using Tumor-infiltrating T Cellsmentioning

confidence: 99%

Immunological aspect of the liver and metastatic uveal melanoma

Terai¹,

Mastrangleo²,

Sato³

2017

JCMT

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Uveal (eye) melanoma is the most common primary eye malignancy in adults. Despite optimal treatments for primary uveal melanoma, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Once hepatic metastasis develops, the survival of patients is generally short and currently available treatments fail to show meaningful improvement of survival. Recent development of immune checkpoint blockades revolutionized immunotherapy for metastatic cutaneous (skin) melanoma. Unfortunately, metastatic uveal melanoma is unresponsive to this approach, thus there is an unmet need to improve the treatment of metastatic uveal melanoma. One unique characteristic of uveal melanoma is that the majority of metastases first develop in the liver. The liver is highly specialized in development of immune tolerance to food-derived antigens and consequently serves a unique function in the immune system. Understanding the mechanisms by which the liver orchestrates immune-related responses is important to the development of an effective immunotherapy for hepatic metastases such as metastatic uveal melanoma. In this review article, the authors overview the immunological aspects of the liver and discuss approaches to improve immunotherapy for metastatic uveal melanoma. Key words:Uveal melanoma, metastasis, liver, liver microenvironment, immunotherapy ABSTRACTArticle history:

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“…This is particularly true for patients with modestly mutated cancers arising from epithelial organs, collectively the leading causes of adult cancer‐related deaths . Detailed immune monitoring studies of exceptional patient responders to immunotherapy have revealed three critical variables that simultaneously must be satisfied for cancer regression to occur . First, the patient must possess a repertoire of T cells capable of recognizing antigens displayed on the surface of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study

Cited by 238 publications

References 35 publications

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

Immunological aspect of the liver and metastatic uveal melanoma

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

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