T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma

Abstract

Background: Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes.

Methods: We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab. Statistics from these repertoires were then tested for their association with clinical response and treatment group.

Results: We demonstrate that, first, the majority of patients receiving these treatments experience a net diversification of their peripheral TCR repertoires. Second, patients receiving ipilimumab experienced larger changes in their repertoires, especially in combination with GVAX. Finally, both a low baseline clonality and a high number of expanded clones following treatment were associated with significantly longer survival in patients who received ipilimumab but not in patients receiving nivolumab.

Conclusions: We show that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and demonstrate the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy. In addition, our results suggest testing sequential administration of anti-CTLA-4 and anti-PD-1 antibodies to achieve optimal therapeutic benefit.

Trial registration: Samples used in this study were collected from the NCT00836407 and NCT02243371 clinical trials.

Funding: Research supported by a Stand Up To Cancer Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research grant (SU2C-AACR-DT14-14). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (AACR). Additional clinical trial funding was provided by AACR-Pancreatic Cancer Action Network Research Acceleration Network grant (14-90-25-LE), NCI SPORE in GI Cancer (CA062924), Quick-Trials for Novel Cancer Therapies: Exploratory Grants (R21CA126058-01A2), and the US Food and Drug Administration (R01FD004819). Research collaboration and financial support were provided by Adaptive Biotechnologies.

Keywords: Cancer immunotherapy; Immunology; Oncology; T-cell receptor.

Conflict of interest statement

Conflict of interest: EMJ receives research funding from Bristol-Myers Squibb and Aduro Biotech, is on the advisory board for Genocea Biosciences, and has the potential to receive royalties from Aduro Biotech. DTL receives research funding from Bristol-Myers Squibb, Merck, and Aduro Biotech; is on advisory boards for Bristol-Myers Squibb and Merck; and received a speaker honorarium from Merck. MY receives research grants from Bristol-Myers Squibb, Merck, and Exelixis. HSR has consultancy, equity, ownership, multiple patents (RU Patent No. 2539032; US Patent No. 9181590, and more), and royalties with Adaptive Biotechnologies. ECY and JAR have employment and equity with Adaptive Biotechnologies.

Figures

Figure 1. Sample clonality of all patients separated by arm and time point.

Anti–CTLA-4 study patients are shown in blue; anti–PD-1 study patients are shown in green. Red bars represent the mean and 95% confidence interval.

Figure 2. Overlap between pre- and posttreatment samples.

Left: the Morisita distance between pre- and posttreatment; 3 samples for each patient. Patients are separated by treatment arm. Right: scatter plots showing the abundance of each clone before and after treatment, from 2 representative patients with low (bottom) and high (top) Morisita index. Blue arrows indicate which repertoires are shown to the right. Red bars represent mean and 95% CI. A Wilcoxon signed-rank test was used to assess significance. ***P < 0.00005.

Figure 3. The sample clonality of patients separated by study and response.

The left panel shows pretreatment samples; the right panel shows posttreatment samples. Red bars represent mean and 95% CI. A Wilcoxon signed-rank test was used to assess significance. *P < 0.05.

Figure 4. Number of expanded clones in patients separated by study and response.

The number of clones significantly expanded from baseline to posttreatment in all patients, separated by clinical response and study. Red bars represent mean and 95% CI. A Wilcoxon signed-rank test was used to assess significance. *P < 0.05.

Figure 5. Kaplan-Meier survival curves for patients on the anti–CTLA-4 study (top, in blue) or the anti–PD-1 study (bottom, green).

In the left column, patients are separated by clonality status (<0.1, diverse; >0.1, clonal). In the right column, patients are separated by high (>100) or low (<100) number of expanded clones. A likelihood ratio test was used to assess significance.

Figure 6. Timeline of the NCT00836407 (top) and NCT02243371 (bottom) clinical trials.

Black arrows indicate treatments. Red arrows indicate blood draws used in this study. Black text indicates treatments received by patients in both arms; blue text represents only patients in the combination arm. Numbers at left indicate the number of samples analyzed for each time point, arm, and study. LM, Listeria monocytogenes.