|Year : 2020 | Volume
| Issue : 1 | Page : 1-2
Immune checkpoint therapy: A paradigm shift in combination with curative potential
Department of Surgery, Division of Urology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan
|Date of Submission||13-Jan-2020|
|Date of Web Publication||20-Feb-2020|
Dr. Tai-Lung Cha
Department of Surgery, Division of Urology, National Defense Medical Center, Tri-Service General Hospital, No. 325, Sec. 2, Chenggong Rd., Neihu District, Taipei City 11490
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Cha TL. Immune checkpoint therapy: A paradigm shift in combination with curative potential. Urol Sci 2020;31:1-2
The advancement of research on two fronts has facilitated the development of more efficient therapies that provide significant clinical benefit to cancer patients. One area originates from a fundamental understanding of gene mutations that activate or inactivate signaling pathways that drive cancer development. This work promoted the development of targeted therapies that bring clinical responses in the majority of patients bearing the driver mutations, although the responses duration is often limited. In the second front is the advances in detailed knowledge of molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These improvements led to the successful therapeutics targeting immune checkpoints to unleash anti-tumor T-cell responses, resulting in durable, long-lasting responses but only in a fraction of patients.
Cancer immunotherapy harnessing an antitumor immune response has primarily focused on amplifying immune activation mechanisms that are employed in human encountered invaders such as viruses and bacteria. This “immune enhancement” strategy has achieved higher objective response rates in cancer patients with fewer immune-related adverse events (irAEs) by targeting the CTLA4 and B7-H1/programmed death 1 (PD-1) pathways. These immune checkpoint blockade therapies that aim to reactivate tumor-induced immune deficiency selectively targeting T-cell response in the tumor microenvironment, which has led to their Food and Drug Administration approval in clinical indication for more than 10 cancer types. These more beneficial tumor response-to-toxicity profiles further facilitated their combination with different therapies. In this issue, there are two mini-review articles highlight the evolution and progress of immune therapies in metastatic clear cell renal cell carcinoma (ccRCC) and elaborate the combination of the immune checkpoint inhibitor (ICI) with conventional therapeutic agents in genitourinary tract (GU) cancers, respectively.
Hsueh and Tsai reviewed that the immune therapeutic evolution of metastatic renal cell carcinoma (mRCC), especially clear cell subtype, based on their characteristics with immunogenic responsiveness. ccRCC, the most common histological subtype (60%), which is characterized by increased angiogenesis through the activation of the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin pathways. Although the first-line antiangiogenic therapies do benefit mRCC patients, the durable response is uncommon for intermediate/poor-risk patients. The role of the immune system in mRCC was first explored through the use of immunoregulatory cytokines, including interferon-α and interleukin-2 two decades ago. However, their clinical implementation is limited due to the modest clinical benefits and high incidence of severe adverse events. Since CTLA-4 and PD-1 regulate different inhibitory pathways on T cells, monoclonal antibody therapy targeting each or both molecules was tested and found to improve the overall survival (OS) of mRCC patients. Another mini-review reported by Guo and Lin focused on the combinations of the blockade with conventional therapeutic agents and ICIs in GU tract cancers. Anti-PD therapy is an immune normalization approach which provides an inherent and significant advantage to facilitate its use in combinatorial treatment in the context of its broad therapeutic effect and minimal toxicity.
Combined ICIs with either VEGF monoclonal antibody (atezolizumab + bevacizumab) or specific VEGF-targeted therapy (pembrolizumab + axitinib; avelumab + axitinib) showed a significant increase of ORR and OS in the first-line setting of mRCC patients. Despite the promising efficacy of ICI and anti–VEGF combination therapies, some issues need to be considered. First, the high incidence of treatment-related adverse events is a concern. More specific antiangiogenic agents such as monoclonal antibody or small spectrum VEGFR tyrosine kinase inhibitors may potentiate ICIs therapeutic efficacy but not worsen combined therapy-induced adverse event profiles and severity. Therefore, careful choice of combined drugs and the identification of predictive biomarkers are urgently required to balance the benefit and toxicities. Second, whether we should treat mRCC patients with ICI and antiVEGF agents or in sequence in first-line setting remains elusive. Third, there are patients who have primary or acquired resistance after the treatment of ICI. These concerns should be also considered in ICI combination therapy with various therapies of GU tract cancers.
Currently, more than 1500 clinical trials are under investigating that combine anti-PD therapy with nearly all kinds of cancer therapeutics, including chemotherapy, radiotherapy, oncolytic virus, targeted therapy, and other immunotherapies. However, many of these clinical trials are not designed based on the basic principles of anti-PD therapy, and some of them may even impair the effects of anti-PD therapies. From a mechanistic perspective, it has been proposed that combination strategies with immune checkpoint therapies and genomically targeted agents will contribute to the induction of immune memory, resulting in more durable tumor control than what is achievable with either treatment modality. “Cancer vaccines” induced by genomically targeted therapies with high objective response rates actually could be attributed to inducing the killing of tumor cells and resulting in the release of tumor antigens and neoantigens, which can be subsequently presented by antigen-presenting cells to tumor-specific T cells. The future direction of combination cancer immunotherapies should mainly be guided by science.
The principles we have learned from the knowledge of the immune checkpoint pathways and the development of ICIs will lead us to design more effective normalization cancer immunotherapies, allowing for optimal adjustment of therapeutic combination and to extend the frontiers of more successful cancer treatment.
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