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Updated: Jan 12, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory
Robert W Lentz1, Julie Lang2, Todd M Pitts1
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Purpose:
In this preclinical human immune system patient-derived xenograft (HIS-PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite-stable (MSS) colorectal cancer.
Patients And Methods:
HIS BALB/c-Rag2nullIl2rγnullSirpαNOD mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS colorectal cancer were treated with triple therapy in a safety run-in (stage 1) followed by expansion (stage 2, planned N = 42). The co-primary objectives were to determine the recommended dose of evorpacept and objective response rate (vs. historic control).
Results:
In HIS-PDX mice, triple therapy decreased the growth of MSS colorectal cancer tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels: N = 12 in stage 1 and N = 4 in stage 2. Trial enrollment was terminated early because of safety concerns (one treatment-related grade 5 event each of hemophagocytic lymphohistiocytosis and cytokine release syndrome). Otherwise, the adverse event profile was as expected. Among all patients, the objective response rate was 6.3%; formal hypothesis testing was not performed. The disease control rate was 12.5%, the median progression-free survival was 2.3 months, and the median overall survival was 10.9 months. Blood- and tumor-based clinical trial correlative analyses identified innate and adaptive immune system activation.
Conclusions:
Whereas triple therapy demonstrated evidence of efficacy in refractory MSS colorectal cancer, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS colorectal cancer.
Significance:
Evorpacept, cetuximab, and pembrolizumab demonstrated antitumor activity in a preclinical HIS-PDX model and clinical trial in refractory MSS colorectal cancer; however, immune-related adverse events prompted early termination of study enrollment. Evidence of innate and adaptive antitumor immune activation was identified. The role of SIRPα/CD47 blockade in the treatment of MSS colorectal cancer needs to be further elucidated in future trials.
Insights
Triple therapy with evorpacept, cetuximab, and pembrolizumab showed antitumor activity in microsatellite-stable colorectal cancer but was halted due to safety concerns. Further research is needed to optimize CD47-targeted therapies for this patient group.
Area of Science:
- Immunotherapy
- Oncology
- Translational Medicine
Background:
- Microsatellite-stable (MSS) colorectal cancer remains a challenge for immunotherapy.
- CD47 blockade is a promising strategy to enhance anti-tumor immunity.
Purpose of the Study:
- To evaluate the safety and efficacy of a triple therapy combining evorpacept (anti-CD47), cetuximab, and pembrolizumab in MSS colorectal cancer.
- To determine the recommended dose of evorpacept in this combination therapy.
Main Methods:
- Preclinical studies using a human immune system patient-derived xenograft (HIS-PDX) model.
- A Phase II clinical trial with a safety run-in and expansion phase in patients with refractory MSS colorectal cancer.
Main Results:
- Triple therapy demonstrated antitumor activity and increased CD8+ T cell infiltration in preclinical models.
- The clinical trial was terminated early due to severe immune-related adverse events (hemophagocytic lymphohistiocytosis and cytokine release syndrome).
- Limited efficacy was observed in patients, with an objective response rate of 6.3%.
Conclusions:
- While the triple therapy showed potential, safety concerns limit its current application in MSS colorectal cancer.
- Further investigation is required to understand the role of SIRPα/CD47 blockade and optimize treatment strategies for MSS colorectal cancer.
