endothelial growth factor by human tumors inhibits the functional
maturation of dendritic cells. Nat Med. 1996;2:1096-103.
12. Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor
affects dendritic cell maturation through the inhibition of nuclear factor
kappa B activation in hemopoietic progenitor cells. J Immunol.
1998;160:1224-32.
13. Huang Y, Chen X, Dikov MM, et al. Distinct roles of VEGFR-1 and
VEGFR-2 in the aberrant hematopoiesis associated with elevated levels
of VEGF. Blood. 2007;110:624-31.
14. Ko JS, Zea AH, Rini BI, et al. Sunitinib mediates reversal of myeloidderived
suppressor cell accumulation in renal cell carcinoma patients.
Clin Cancer Res. 2009;15:2148-57.
15. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression
of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med.
2015;212:139-48.
16. Bouzin C, Brouet A, De Vriese J, Dewever J, Feron O. Effects of vascular
endothelial growth factor on the lymphocyte-endothelium interactions:
identification of caveolin-1 and nitric oxide as control points of
endothelial cell anergy. J Immunol .2007;178:1505-11.
17. Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes
a selective immune barrier promoting tolerance in tumors. Nat
Med. 2014;20:607-15.
18. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon
alfa-2a for treatment of metastatic renal cell carcinoma: a randomised,
double-blind phase III trial. Lancet. 2007;370:2103-11.
19. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon
alfa compared with interferon alfa monotherapy in patients with
metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26:
5422-8.
20. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and
the combination in patients with metastatic renal cell carcinoma: a randomised,
phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:
1473-82.
21. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab
versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J
Med. 2018.
22. Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination
with pembrolizumab in patients with advanced renal cell cancer: a nonrandomised,
open-label, dose-finding, and dose-expansion phase 1b
trial. Lancet Oncol. 2018;19:405-15.
23. Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab
plus axitinib as first-line therapy in patients with advanced clear-cell
by engaging commercial companies. However, how tumor
profiling influences decision making and outcome in RCC
is unclear. The issues of heterogeneity and tumor evolution
also remain a trap on our journey to treatment, as often
analyzed specimens come from a small component from
the archival nephrectomy specimen. To overcome these
barriers, understanding the disease at time of treatment
decisions may be critical to determine if new mutations
have developed and been selected for.
In a hypothesis-generating report Pal, et. al. looked at
circulating tumor DNA (ctDNA) from a nationwide cohort
of 220 consecutive patients with mRCC. Results suggest
that the acquisition of additional genomic alterations can
be a mechanism of resistance to therapy that hopefully
could be targeted in the future. The noninvasive nature of
ctDNA testing makes it an attractive method of obtaining
real time genomic data as compared to serial biopsies of
metastatic sites progressing through therapy. It also
provides insight into acquisition of additional driver
alterations during the course of tyrosine kinase therapy,
which if confirmed may suggest a role for therapy prior to
checkpoint inhibitors to increase immunogenicity and
82 Kidney Cancer Journal
perhaps improve response to therapy. As increased
genomic alterations can be a surrogate for mutational burden,
shown to be correlated with increased neoantigen
formation and improved response to immunotherapies,
these insights may suggest a role for TKI prior to immune
checkpoint inhibitors. The article in this issue by Drs.
McGregor, Choueiri, and Flippot briefly covers this topic
and reports and explores how this emerging biomarker
may be an exciting avenue for further biomarker work.
I hope I have provided you a taste of some of the exciting
topics to be covered in depth at the IKCS in November.
Attendees at the symposium will come away with not only
new insights on this subject but on many other findings
with translational impact. These include point-counterpoint
discussions and Q&A sessions on highly controversial
areas, from the bench to the bedside. There is still time
to register and make plans to attend the most comprehensive
kidney cancer meeting of the year. You can find details
by going to the Kidney Cancer Association website:
https://www.kidneycancer.org/event/17th-internationalkidney
cancer-symposium. See you in Miami!
Brian M. Shuch, MD
Guest Editor
GUEST EDITOR’S MEMO
(continued from page 70)
renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding
and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19:451-60.
24. Lee C, Makker V, Rasco D, et al. Lenvatinib + pembrolizumab in patients
with renal cell carcinoma: Updated results. J Clin Oncol. 36, 2018
(suppl; abstr 4560).
25. Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion
cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and
CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic
urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.
J Clin Oncol. 36, 2018 (suppl 6S; abstr 515).
26. Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti-PD-1; BMS-
936558, ONO-4538) in combination with sunitinib or pazopanib in patients
(pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol.
32:5s, 2014 (suppl; abstr 5010).
27. Chowdhury S, McDermott DF, Voss MH, et al. A phase I/II study to
assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab
(PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J
Clin Oncol. 35, 2017 (suppl; abstr 4506).
28. Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination
with bevacizumab enhances antigen-specific T-cell migration in
metastatic renal cell carcinoma. Nat Commun 2016;7:12624.
29. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and
molecular correlates of response to atezolizumab alone or in combination
with bevacizumab versus sunitinib in renal cell carcinoma. Nat
Med. 2018;24:749-57.
30. Boyerinas B, Jochems C, Fantini M, et al. Antibody-Dependent Cellular
Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab
(MSB0010718C) on Human Tumor Cells. Cancer Immunol Res. 2015;3:
1148-57.
31. McDermott DF, Lee J, Szczylik C, et al. Pembrolizumab monotherapy
as first-line therapy in advanced clear cell renal cell carcinoma (accRCC):
Results from cohort A of KEYNOTE-427. J Clin Oncol. 36, 2018
(suppl; abstr 4500).
32. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:
1803-13.
33. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival
with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N
Engl J Med 2017;377:1345-56.
34. Manson G, Norwood J, Marabelle A, Kohrt H, Houot R. Biomarkers
associated with checkpoint inhibitors. Annals of Oncology 2016;27:
1199-206. KCJ