Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling
- The Houston Methodist Research Institute, United States
- The University of Texas MD Anderson Cancer Center, United States
- University of Texas Health Science Center, United States
- Brigham and Women's Hospital, United States
- Baylor College of Medicine, United States
- Rutgers University, United States
- Harvard Medical School, United States
- Rutgers Cancer Institute of New Jersey, United States
- University of Texas MD Anderson Cancer Center, United States
Abstract
Background: Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies.
Methods: Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials.
Results: The derived parameters Λ and µ were both significantly different between responding versus non-responding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within two months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology.
Conclusion: These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.
Funding: We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (Z.W., V.C.), the National Institutes of Health (NIH) 1R01CA253865 (Z.W., V.C.), 1U01CA196403 (Z.W., V.C.), 1U01CA213759 (Z.W., V.C.), 1R01CA226537 (Z.W., R.P., W.A., V.C.), 1R01CA222007 (Z.W., V.C.), U54CA210181 (Z.W., V.C.), and the University of Texas System STARS Award (V.C.). B.C. acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). E.K. has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). M.F. was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. R.P. and W.A. received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to S.H.C. (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to P.Y.P. (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Data availability
No new clinical patient data was produced in this study. Data used that was obtained from literature is available in the original publications; we have been careful to cite each of these in the manuscript. Interested researchers should reach out directly to the primary authors of these studies. Data for the in-house clinical trial cohort are from the study reported in PMC7555111; interested researchers should contact the authors of this publication with any data requests.
Article and author information
Author details
Funding
National Science Foundation (DMS-1930583)
- Zhihui Wang
- Vittorio Cristini
European Commission (SER Cymru II Programme)
- Bruna Corradetti
National Institutes of Health (U01CA200468)
- Eugene J Koay
National Institutes of Health (R01CA222959)
- Mauro Ferrari
DOD Breast Cancer Research (Breakthrough Level IV Award W81XWH-17-1-0389)
- Mauro Ferrari
AngelWorks
- Renata Pasqualini
- Wadih Arap
Gillson-Longenbaugh Foundation
- Renata Pasqualini
- Wadih Arap
Marcus Foundation
- Renata Pasqualini
- Wadih Arap
National Institutes of Health (R01CA109322)
- Shu-Hsia Chen
National Institutes of Health (R01CA127483)
- Shu-Hsia Chen
National Institutes of Health (R01CA208703)
- Shu-Hsia Chen
National Institutes of Health (1R01CA253865)
- Zhihui Wang
- Vittorio Cristini
National Institutes of Health (R01CA140243)
- Ping-Ying Pan
National Institutes of Health (R01CA188610)
- Ping-Ying Pan
National Institutes of Health (1U01CA196403)
- Zhihui Wang
- Eugene J Koay
- Vittorio Cristini
National Institutes of Health (1U01CA213759)
- Zhihui Wang
- Vittorio Cristini
National Institutes of Health (1R01CA226537)
- Zhihui Wang
- Renata Pasqualini
- Wadih Arap
- Vittorio Cristini
National Institutes of Health (1R01CA222007)
- Zhihui Wang
- Vittorio Cristini
National Institutes of Health (U54CA210181)
- Zhihui Wang
- Mauro Ferrari
- Shu-Hsia Chen
- Ping-Ying Pan
- Eugene J Koay
- Vittorio Cristini
National Institutes of Health (P30CA016672)
- David S Hong
- James W Welsh
- Eugene J Koay
National Institutes of Health (P30CA072720)
- Steven K Libutti
- Shridar Ganesan
- Renata Pasqualini
- Wadih Arap
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: In-house patient cohort were obtained as de-identified data from a study conducted in accordance with the U.S. Common Rule and with Institutional Review Board Approval at MD Anderson (2014-1020), including waiver of informed consent. This work has been published in J Immunother Cancer. 2020; 8(2): e001001. PMC7555111. doi: 10.1136/jitc-2020-001001
Copyright
© 2021, Butner et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling
eLife 10:e70130.
https://doi.org/10.7554/eLife.70130
Further reading
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- Medicine
Background: Several fields have described low reproducibility of scientific research and poor accessibility in research reporting practices. Although previous reports have investigated accessible reporting practices that lead to reproducible research in other fields, to date, no study has explored the extent of accessible and reproducible research practices in cardiovascular science literature.
Methods: To study accessibility and reproducibility in cardiovascular research reporting, we screened 639 randomly selected articles published in 2019 in three top cardiovascular science publications: Circulation, the European Heart Journal, and the Journal of the American College of Cardiology (JACC). Of those 639 articles, 393 were empirical research articles. We screened each paper for accessible and reproducible research practices using a set of accessibility criteria including protocol, materials, data, and analysis script availability, as well as accessibility of the publication itself. We also quantified the consistency of open research practices within and across cardiovascular study types and journal formats.
Results: We identified that fewer than 2% of cardiovascular research publications provide sufficient resources (materials, methods, data, and analysis scripts) to fully reproduce their studies. Of the 639 articles screened, 393 were empirical research studies for which reproducibility could be assessed using our protocol, as opposed to commentaries or reviews. After calculating an accessibility score as a measure of the extent to which an article makes its resources available, we also showed that the level of accessibility varies across study types with a score of 0.08 for Case Studies or Case Series and 0.39 for Clinical Trials (p = 5.500E-5) and across journals (0.19 through 0.34, p = 1.230E-2). We further showed that there are significant differences in which study types share which resources.
Conclusion: Although the degree to which reproducible reporting practices are present in publications varies significantly across journals and study types, current cardiovascular science reports frequently do not provide sufficient materials, protocols, data, or analysis information to reproduce a study. In the future, having higher standards of accessibility mandated by either journals or funding bodies will help increase the reproducibility of cardiovascular research.
Funding: Authors Gabriel Heckerman, Arely Campos-Melendez, and Chisomaga Ekwueme were supported by an NIH R25 grant from the National Heart, Lung and Blood Institute (R25HL147666). Eileen Tzng was supported by an AHA Institutional Training Award fellowship (18UFEL33960207).
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- Cell Biology
- Medicine
Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
