3430 - Evaluation of immune responses among responders (R) and non-responders (non-R) in a humanized mouse model with colorectal cancer (CRC) xenografts treated with combination immunotherapy

Background

Immune checkpoint inhibition monotherapy has shown no efficacy in microsatellite-stable (MSS) CRC. Combination strategies are being studied to increase the immunogenicity of this cold tumor. Humanized mice are promising models to evaluate immunotherapy combinations and their effects in the engrafted human immune system.

Methods

3 MSS CRC patient-derived xenografts were injected subcutaneously into 68 mice previously humanized through CD34+ cord blood-derived hematopoietic cell transplantation. Mice were allocated into 4 equivalent groups based on human chimerism detected in the blood and subsequently treated with anti-PD-1 therapy and/or multi-tyrosine kinase inhibition. At harvest, flow cytometry immune data from the lymph nodes (LN), the spleen (SP) and tumor-infiltrating lymphocytes (TIL) were analyzed. Mice were classified according to the specific growth rate (SGR, % volume / day) of their tumor/s into R (under median SGR) vs non-R (over median SGR).

Results

50 mice were considered either R (26) or non-R (24). In the peripheral immune organs (LN and SP), the total number of immune cells was similar between R and non-R mice. However, a higher percentage of human and T cells was found in the SP of R mice. Interestingly, the percentage of B cells was higher in the LN and SP of non-R mice. In contrast, in the tumor, an increased number of human cells (mostly T cells) was found in R mice. Notably, CD8+ T cells were significantly higher among TILs. A linear regression analysis was performed, and the number of human and T (CD4+ and CD8+) cells in the tumor significantly decreased (P<.001for all of them) with an increasing tumor SGR.Table: 1904P

T-test on Ln-transformed values

Conclusions

Different immune responses were observed both in the periphery and in the tumor between R and non-R mice. The humanized mouse model appears to be a valid model to evaluate immunotherapy combinations for MSS CRC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Colorado, Anschutz Medical Campus.

Funding

University of Colorado, Anschutz Medical Campus.

Disclosure

All authors have declared no conflicts of interest.