scholarly journals The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory

2018 ◽  
Author(s):  
Jeffrey West ◽  
Mark Robertson-Tessi ◽  
Kimberly Luddy ◽  
Derek S. Park ◽  
Drew F.K. Williamson ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Checkpoint Inhibitor ◽  
Prognostic Index ◽  
Metastatic Potential ◽  
Tumor Burden ◽  
Matrix Game ◽  
Essential Components

AbstractAn upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 ER+breast cancer combines an aromatase inhibitor and a PD-L1 checkpoint inhibitor, and aims to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We develop a mathematical model of the essential components of the PEPI score in order to identify successful combination therapy regimens that minimize both tumor burden and metastatic potential, based on time-dependent trade-offs in the system. We consider two molecular traits, CCR7 and PD-L1 which correlate with treatment response and increased metastatic risk. We use a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded into an ecological model of tumor population growth dynamics. The resulting model predicts both evolutionary and ecological dynamics that track with changes in the PEPI score. We consider various treatment regimens based on combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was found to be a 1 month kick start of the immune checkpoint inhibitor followed by five months of continuous combination therapy. Relative to a protocol with both therapeutics given together from the start, this delayed regimen results in transient sub-optimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final five months of therapy. The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

scholarly journals The Immune Checkpoint Kick Start: Optimization of Neoadjuvant Combination Therapy Using Game Theory

2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jeffrey West ◽  
Mark Robertson-Tessi ◽  
Kimberly Luddy ◽  
Derek S. Park ◽  
Drew F.K. Williamson ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Checkpoint Inhibitor ◽  
Prognostic Index ◽  
Metastatic Potential ◽  
Tumor Burden ◽  
Matrix Game ◽  
Essential Components

Purpose In an upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 estrogen receptor–positive breast cancer, treatment with an aromatase inhibitor and a PD-L1 checkpoint inhibitor combination will be investigated to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We have developed a mathematical model of the essential components of the PEPI score to identify successful combination therapy regimens that minimize tumor burden and metastatic potential, on the basis of time-dependent trade-offs in the system. Methods We considered two molecular traits, CCR7 and PD-L1, which correlate with treatment response and increased metastatic risk. We used a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded in an ecological model of tumor population-growth dynamics. The resulting model predicts evolutionary and ecological dynamics that track with changes in the PEPI score. Results We considered various treatment regimens on the basis of combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was a 1-month kick start of the immune checkpoint inhibitor followed by 5 months of continuous combination therapy. Relative to a protocol giving both therapeutics together from the start, this delayed regimen resulted in transient suboptimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final 5 months of therapy. Conclusion The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

scholarly journals Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuyin Fu ◽  
Yujia Peng ◽  
Shengyan Zhao ◽  
Jun Mou ◽  
Lishi Zeng ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Kinase Inhibitor ◽  
Tumor Regression ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Combination Strategy ◽  
M2 Phenotype

Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.

scholarly journals Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

2021 ◽  
Vol 9 (5) ◽  
pp. e001942
Author(s):  
Xu Yang ◽  
Ying Hu ◽  
Keyan Yang ◽  
Dongxu Wang ◽  
Jianzhen Lin ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Outcome ◽  
Risk Score ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Copy Number Variations ◽  
Risk Scores ◽  
Free Dna

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.ResultsBased on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).ConclusionsThe CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.

Association Between Clinical Tumor Burden and Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non–Small-Cell Lung Cancer

2020 ◽  
Vol 21 (5) ◽  
pp. e405-e414
Author(s):  
Taichi Miyawaki ◽  
Hirotsugu Kenmotsu ◽  
Keita Mori ◽  
Eriko Miyawaki ◽  
Nobuaki Mamesaya ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Tumor Burden ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge

2020 ◽  
Author(s):  
Laetitia Douguet ◽  
Serena Janho dit Hreich ◽  
Jonathan Benzaquen ◽  
Laetitia Seguin ◽  
Thierry Juhel ◽  
...  
Keyword(s):  
Small Molecule ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Tumor Regression ◽  
Checkpoint Inhibitor ◽  
Positive Modulator ◽  
Novel Strategy ◽  
Nsclc Patients ◽  
Improve Patient ◽  
Complete Tumor

ABSTRACTOnly a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.

Sign in / Sign up

Export Citation Format

Share Document