Editing Metastatic Kidney Cancer (section)

== Immunologic approaches in the management of advanced clear cell RCC ==

* '''Cytokines'''
** '''Interferons'''
*** IFN-α was one of the earliest cytokines to be evaluated for activity in RCC
*** '''Response rate generally 10-15%'''
*** '''Durable complete responses are relatively rare (<2%)''' based on limited long-term survival data
*** Despite its '''relatively modest activity compared with IL-2''', IFN was often the agent of choice in the initial treatment of metastatic RCC (until the advent of VEGF pathway antagonists) due to its relative ease of administration compared to IL-2
** '''High-dose Interleukin-2 (IL-2)'''
*** '''Response rates generally 15-20%'''
*** '''Complete responses are seen in 7-9% of metastatic clear cell RCC patients''', with the majority of these remaining disease-free for long periods
*** There are no randomized phase 3 studies demonstrating survival benefit with IL-2.
*** '''Considerable associated toxicity has limited widespread use.'''
**** Vascular leak syndrome and the resulting hypotension, third-space fluid retention, respiratory compromise, and multiorgan damage are some of the potential serious sequelae and led to an unacceptably high treatment-related mortality rate (2-5%)
*** 2 RCTs demonstrated that, although well tolerated, '''lower-dose regimens are associated with lower overall response rates''', as well as with fewer durable, complete responses. Based on these data, '''only high-dose IL-2 regimens are recommended in patients being considered for cytokine therapy'''
*** '''Patients with ccRCC appear most likely to benefit from IL-2; the efficacy of IL-2 has not been adequately evaluated in patients with non–clear cell histologies'''
* Combination IL-2 and interferon
** In a randomized phase 3 study, the combination of IL-2 and interferon was associated with a higher response rate than either agent given alone, although this did not translate to an improved long-term outcome (overall survival) in the combination arm.
* Allogeneic Hematopoietic Stem Cell Transplantation
** Remains an experimental approach in the management of RCC
* '''Immune “checkpoint” inhibitors'''
** '''RCC has only modest response to traditional chemotherapeutics'''
** '''P-glycoprotein'''
*** A transmembrane protein
*** Expressed by 80% to 90% of RCCs
*** '''Acts as an energy-dependent efflux pump for a wide variety of large hydrophobic compounds, including several cytotoxic drugs.'''
** '''The response of RCC to immunomodulators''' (IL-2, IFN-α, and tumor-infiltrating lymphocytes) '''demonstrates an important role for the immune system in the tumor biology of RCC.'''
*** The host immune response to tumors is a highly complex process that is regulated at multiple levels. The interplay between multiple stimulatory and inhibitory processes determines the nature and extent of the antitumor response generated by the host immune system.
*** '''The estimated incidence of spontaneous regression of RCC is between 0.3-1%'''
** It has become increasingly evident that several inhibitory receptors on effector immune cells, such as CD8+ T lymphocytes, play a key role in tightly regulating the immune response to tumors. Furthermore, antitumor responses can be downregulated by activation of T-cell receptors such as cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) and those mediating programmed death-1 (PD-1).
** '''Pharmacologic targeting of immune checkpoints such as CTLA-4 and the PD-1 axis is being explored currently in many solid tumors, including RCC'''
*** CTLA-4 expression on the surface of activated T cells halts the immune response to the tumor. '''Blockade of CTLA-4, such as by the CTLA-4 antibody ipilimumab,''' '''leads to major tumor responses''', but also significant potential toxicity
*** PD-1 and PD-1 ligand–1 pathway lead to decreased effector T-cell activity. '''Blockade of''' '''PD-1, such as by the PD-1 antibodies nivolumab and pembrolizumab, has been associated with significant clinical response'''
*** '''CheckMate 214'''
**** '''Randomized 1096 patients with previously untreated clear-cell advanced renal-cell carcinoma to nivolumab + ipilimumab vs. sunitinib'''
***** Mostly intermediate or poor-risk patients
**** '''OS and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib''' among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma
**** Motzer, Robert J., et al."Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma." New England Journal of Medicine 378.14 (2018): 1277-1290.
*** '''CheckMate 9ER'''
**** '''Randomized 651 patients with previously untreated clear-cell advanced renal-cell carcinoma to nivolumab + cabozantinib vs. sunitinib'''
**** '''OS and progression-free survival were significantly higher with nivolumab plus cabozantinib than with sunitinib'''
**** Choueiri, Toni K., et al."Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma." ''New England Journal of Medicine'' 384.9 (2021): 829-841.
*** '''CLEAR'''
**** '''Randomized 1069 patients with advanced renal cell carcinoma and no previous systemic therapy to lenvatinib + pembrolizumab vs. lenvatinib + everolimus vs. sunitinib'''
**** '''OS and progression-free survival were significantly higher with lenvatinib + pembrolizumab'''
**** Motzer, Robert, et al."Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma." ''New England Journal of Medicine'' 384.14 (2021): 1289-1300.