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

It’s now been 3.5 years since I last wrote anything about testicular germ cell tumors and ongoing clinical trials.1  Although 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 cell7 and 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 host’s 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
  • Nivolumab + Ipilumumab for advanced rare genitourinary tumors (NCT03333616)
  • Durvalumab + Tremelimumab for relapsed/refractory germ cell tumors (NCT03158064)
  • Durvalumab alone or + Tremelimumab in refractory germ cell tumors (APACHE) (NCT03081923)
  • Pembrolizumab in rare unresectable or metastatic tumors (NCT02721732)
  • In situ vaccination of Tremelimumab and IV Durvalumab in patients with advanced, measurable, and biopsy-accessible cancers (NCT02643303)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References:
  1. Yu EY. "Are there clinical trials for relapsed or refractory germ cell tumors?" Urotoday Clinical Trials Portal. September 8, 2017.
  2. Rajpert-De Meyts E, et al."Testicular germ cell tumours" Lancet 2016; 387:1762-74.
  3. De Giorgi U, et al. "Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features" Urol Oncol 2011; 29:284-90.
  4. Einhorn LH, et al. "High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-Cell Tumors" N Engl J Med 2007; 357:340-8.
  5. Kollmannsberger C, et al. "Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group" J Clin Oncol 2004; 22:108-14.
  6. Ramos JD and Yu EY. "Immuno-oncology in urothelial carcinoma: who or what will ultimately sit on the iron throne?" Immunotherapy. 2017; 9:951-4.
  7. Alsharedi M and Katz H."Check point inhibitors a new era in renal cell carcinoma treatment" Med Oncol 2018; 35:85.
  8. Wong RL nand Yu EY. "Refining Immuno-Oncology Approaches in Metastatic Prostate Cancer: Transcending Current Limitations" Curr Treat Options Oncol. 2021; 22:13.
  9. Dorantes-Heredia R, et al. "Spontaneous regression as a ‘burned-out’ non-seminomatous testicular germ cell tumor: a case report and literature review" J Surg Case Rep. 2019; 2019:rjy358.
  10. Frankhauser CD, et al. "Frequent PD-L1 expression in testicular germ cell tumors" Br J Cancer. 2015; 113:411-3.
  11. Jennewein L, et al. "Increased tumor vascularization is associated with the amount of immune competent PD-1 positive cells in testicular germ cell tumors" Oncol Lett 2018; 15:9852-60.
  12. Lobo J, et al. "Detailed Characterization of Immune Cell Infiltrate and Expression of Immune Checkpoint Molecules PD-L1/CTLA-4 and MMR Proteins in Testicular Germ Cell Tumors Disclose Novel Disease Biomarkers" Cancers (Basel) 2019; 11:1535.
  13. Siska PJ, et al. "Deep exploration of the immune infiltrate and outcome prediction in testicular cancer by quantitative multiplexed immunohistochemistry and gene expression profiling" Oncoimmunology 2017; 6:e1305535.
  14. Shah S, et al. "Clinical Response of a Patient to Anti–PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors" Cancer Immunol Res 2016; 4:903-9.
  15. Chi EA and Schweizer MT. "Durable response to immune checkpoint blockade in a platinum-refractory patient with nonseminomatous germ cell tumor" Clin Genitourin Cancer 2017; 15:e855-e7.
  16. Zschabitz S, et al. "Response to anti-programmed cell death protein-1 antibodies in men treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and stem cell transplantation" Eur J Cancer 2017; 76:1-7.
  17. Adra N, et al. "Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206" Ann Oncol. 2018; 29:209-14.
  18. Mego M, et al. "Phase II study of avelumab in multiple relapsed/refractory germ cell cancer" Invest New Drugs 2019; 37:748-54.
  19. Necchi A, et al. "An Open-label Randomized Phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): Results from the First Planned Interim Analysis" Eur Urol. 2019; 75:201-3.

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