The VEGFR inhibitor pazopanib was efficacious independent of T-cell receptorâ€“gamma entropy in metastatic renal cell carcinoma setting.
Thai Ho, MD, PhD
Renal cell carcinoma (RCC) with higher entropy, a measure of T-cell diversity, may portend a favorable prognosis. However, in a randomized clinical study, the VEGFR inhibitor pazopanib (Votrient) was efficacious independent of T-cell receptor (TCR)—gamma entropy in metastatic RCC setting, according to data presented at the 2016 Genitourinary Cancers Symposium.
“High entropy may represent a broader response to tumor antigens,” said Thai Ho, MD, PhD, medical oncologist, Mayo Clinic, Scottsdale, Arizona.
The T-cell repertoire appears to affect response to VEGFR blockade. An inverse relationship exists between the suppression of immune surveillance and activation of the VEGFR pathway, Ho explained. Further, an increase of PD-L1 is associated with decreased overall survival, regardless of whether patients are treated with VEGFR blockade.
During the process of being exposed to various antigens or pathogens during T-cell maturation, rearrangements of the complementary determining region (CDR3) are critical to mount the immune response. These regions of the genome that undergo recombination generate diversity. Each CDR3 nucleotide sequence is a unique tag for clonal descendants.
Ho’s group looked at the association between the T-cell repertoire and outcome in patients with metastatic RCC receiving either pazopanib or placebo. The T-cell repertoires were analyzed in pretreatment RCC tumor specimens for both TCR-gamma and TCR-beta CDR3 regions using Adaptive Biotechnology’s ImmunoSEQ assay.
“When we evaluate the immune repertoire profiling by T-cell receptor sequencing, we can look at clonality,” said Ho. “Clonality describes the diversity of T cells or B cells within a given population.”
With low clonality, or a clonality value of 0, each clone has a different TCR sequence. In the setting of high clonality (a value of 1), however, all of the TCR sequences are identical.
“Essentially, an increased clonality represents a restricted T-cell clone and could potentially lead to increased antigen escape,” he said.
Another measure of diversity is entropy, which represents the diversity of the nucleotide sequences. In the setting of low entropy, in which a tumor expresses several neoantigens, some of them driving versus non-driving neo-antigens, TCR specificity is low. “However, in the setting of high entropy, you have multiple T-cell receptor sequences that may bind to multiple tumor antigens,” said Ho. “So in the setting of increased entropy, it may represent a broader T-cell population and may have less antigen escape.”
The open-label crossover study enrolled 435 patients who were randomized 2:1 to receive pazopanib or placebo. Patients had the option of receiving pazopanib at the time of disease progression. Associations between the TCR repertoire and pazopanib efficacy were assessed. Of the original 435 patients in the cohort, 35% were available for TCR-gamma analysis and 25% for TCR-beta analysis.
“We found that TCR-beta and TCR-gamma entropy were highly correlated,” said Ho. “This increased entropy likely represents a broader T-cell population prior to treatment.”
TCR-gamma clonality ranged from 0 to 0.98, and entropy ranged from 0 to 10.37. TCR-beta clonality ranged from 0 to 0.31, and entropy ranged from 1 to 12.1. This increased clonality and decreased entropy may lead to antigen escape due to restricted T-cell populations, according to Ho. A similar trend was observed for TCR-beta.
Patients were subdivided into high entropy and low entropy groups, with high entropy defined as being in the top 25th percentile and low entropy in the bottom 75th percentile. Placebo-treated patients in the low entropy group had a median progression-free survival (PFS) of 4.4 months, whereas placebo-treated patients with high entropy had a median PFS of 12.78 months (P <.0001). Pazopanib attenuated this difference in entropy. “This suggests that placebo-treated patients with higher TCR-gamma have an improved PFS,” said Ho.
“From this exploratory analysis, we can say that RCC samples with higher entropy were associated with a favorable prognosis and may potentially represent a broader immune response to tumor antigens,” he said. “VEGFR blockade with pazopanib was efficacious independent of TCR-gamma entropy, and interestingly, tumors in the placebo arm with lower entropy may have had an unfavorable immune repertoire.”
Ho TH, Gagnon RC, Liu Y, et al. T-cell receptor (TCR) repertoire in metastatic renal cell carcinoma (RCC) patients treated with vascular endothelial growth factor receptor blockade. J Clin Oncol 34, 2016 (suppl 2S; abstr 501).