acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025With much gratitude for discussions from Chris Chidley, Ash Alizadeh, Palmer lab members and others, and support from NCI, NIGMS, @unclineberger.bsky.social, @unc-phco.bsky.social and UNC Computational Medicine Program 13/13 030
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025This model provides quantitative insight into how combination therapy overcomes heterogeneity within and between tumors to cure many patients with Large B-Cell Lymphoma. We hope it is a useful tool to design new curative-intent combinations using clinical data on new drugs. 12/n 110
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025Importantly, first-author Amy Pomeroy had predicted the success of Pola-R-CHP *before* the trial read out, as she reported from the model prototype back in 2021: www.amypomeroy.com/post/predicting-the-results-of-the-polarix-trial 11/nt.cohttps://www.amypomeroy.com/post/predicting-the-results-of-the-polarix-trial 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025Looking at ‘RCHOP+X’ trials, we used clinical data on each ‘drug X’ to predict the clinical trial results. Only Pola-R-CHP, and Tucidinostat plus R-CHOP, were expected to succeed, and indeed they did asco.org/abstracts-pr... nejm.org/doi/full/10.... 10/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025We calibrated the model to reproduce Progression-Free Survival for the CHOP and RCHOP regimens for Diffuse Large B-Cell Lymphoma. Simulated tumor population shrinkage agreed well with observed changes in circulating tumor DNA after the first cycle of RCHOP: 9/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025From this ‘bottom-up’ model of tumor heterogeneity, simulating treatment responses in a cohort of patients produces a Kaplan-Meier curve of Progression-Free Survival: 8/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025This extends to combination therapy by using a different dimension of heterogeneity for each drug This way, patients and cells vary in their sensitivity to different drugs; for example, some patients can be more sensitive to one drug than another, or sensitive to both, etc. 7/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025Extending to patient variability, a group of patients - say in a clinical trial - also have a distribution of drug response phenotypes, with each patient’s cancer containing a range of cellular heterogeneity around the average drug sensitivity of that individual. 6/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025In this model of heterogeneity as a distribution of states, each cycle of chemotherapy progressively shifts the distribution to increasingly drug-resistant states 5/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025Many insightful models of tumor heterogeneity described drug-sensitive and drug-resistant subpopulations. Based on clone-tracing data, we modelled cellular heterogeneity as a distribution of sensitivity phenotypes, reflecting many complex influences on drug response 4/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025We built a model that unifies intra-tumor and inter-patient heterogeneity in drug sensitivity to understand the clinical efficacy of curative-intent combination therapy for Large B-Cell Lymphoma. 3/n 100
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025Cell-to-cell and patient-to-patient heterogeneity both have a role in the success of drug combinations. While inter-patient variation can explain better response rates of combos for incurable cancers, CURES need a regimen to also overcome cellular heterogeneity and evolution 2/n 110
acpalmer.bsky.social @acpalmer.bsky.social · 10/04/2025New paper, with Amy Pomeroy! A model of intratumor and interpatient heterogeneity explains clinical trials of curative combination therapy for lymphoma now out in Blood Cancer Discovery: doi.org/10.1158/2643... #mathonc #lymsm #BloodCancer 1/ndoi.orgA model of intra-tumor and inter-patient heterogeneity explains clinical trials of curative combination therapy for lymphomaAbstract. Models of tumor drug response have illuminated important concepts in oncology, but there remains a need for theory that combines intra-tumor and inter-patient heterogeneity to explain patien... 132
