Will Immunotherapy Work as Salvage Therapy for Patients with Testicular Germ Cell Tumors? – UroToday

Its now been 3.5 years since I last wrote anything about testicular germ cell tumors and ongoing clinical trials.1Although we still cure most men afflicted with this disease, we have not made any major new therapeutic advancements since I wrote that last article. Approximately, 15-20% of patients with metastatic germ cell tumors will relapse following initial chemotherapy. Even in this situation, approximately 50% can still be cured with salvage treatments, either with more conventional cisplatin-based chemotherapy or with high-dose chemotherapy and autologous stem cell rescue.2-4 However, patients with cisplatin-refractory disease or progressive disease following high-dose salvage chemotherapy and autologous stem cell rescue, harbor an extremely dim prognosis. In these situations, palliative chemotherapy, with regimens containing oxaliplatin, is limited in efficacy, and targeted biologic therapies have also shown limited efficacy.5

Immune checkpoint inhibitors have already shown promise in other genitourinary malignancies, such as urothelial,6 renal cell7and even select prostate carcinomas.8 There is also some rationale surrounding the use of immune checkpoint inhibitors for men with treatment-refractory testicular germ cell tumors. For example, spontaneous testicular tumor regressions, commonly called a burned out testicular tumor, can at least partially be attributed to a hosts immune microenvironment, not just alterations in tumor vascularization.9 Additionally, abundant expression of program death-ligand 1 receptor (PD-L1) is present in both seminomas and nonseminomas.10 There is also greater infiltration of PD-1 expressing cells in testicular tumors over normal testicular tissue, and this also has relationship with pathological tumor vasculature that may allow for intratumoral migration of immune cells.11

Immune signatures also provide some indirect insights on the role of the immune system at different stages and prognoses of testicular germ cell tumors. For example, CTLA-4 expression is correlated with better prognostic features, such as decreased lymphovascular invasion and lower disease stage.12 Meanwhile, more advanced stages of disease have an immune-exclusive microenvironment, with decreased T-cell and NK-cell signatures and increased regulatory T cell, neutrophil, mast cell, and macrophage signatures.13

There is emerging data on the clinical efficacy of PD-(L)1 antibody therapy for testicular germ cell tumors. Both pembrolizumab and nivolumab have provided some early hints of efficacy in case reports/series.14-16 Subsequently, 3 clinical trials have been published on this topic. Both pembrolizumab17 and avelumab,18 were tested as monotherapy, and both trials were terminated early due to lack of efficacy. Similarly, the single agent arm of durvalumab, with or without tremelimumab trial, was closed to accrual due to the majority of patients exhibiting hyperprogression.19 Yet, there were some signs of efficacy in the combination arm, with one patient having a partial response and another patient with radiographically stable disease and serum tumor marker decline.

The above data imply that single checkpoint inhibitor therapy is unlikely to make major strides in the field of treatment-refractory testicular germ cell tumors. Yet, there may still be promise for combination therapy. Future approaches may include inhibition of multiple checkpoints, altering the immune exclusive microenvironment, and/or incorporation of agents that alter tumor vascularization to allow more cytotoxic T cells into the tumor microenvironment. As a result, we need to support the development and accrual of more immunotherapy combination clinical trials. Below, I have highlighted some ongoing immunotherapy trials that include patients with treatment-refractory testicular germ cell tumors.

Highlighted Trials

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Will Immunotherapy Work as Salvage Therapy for Patients with Testicular Germ Cell Tumors? - UroToday