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Effects of Macrophage Targeted anti-CCL2 Immunotherapy on Functional Tumor Response

Shelby Bess

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Department of Biomedical Engineering, University of Arkansas

TGIF: Graduate Seminar

October 9, 2020

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  • In 2019
    • 145,000 new cases with 51,000 deaths

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  • 4th most common cancer and 2nd deadliest cancer

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  • 7th worst 5-year survival rate

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Colorectal Cancer (CRC)

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  • Standard: 5-fluorouracil (5-FU) neoadjuvant chemotherapy followed by surgery
  • After treatment, biopsies are used to assess pathologic complete response (pCR)
    • In CRC: < 30% of cases, resulting in recurrence rates of 25% (primary cause of CRC-related deaths)

Treatment Standard

Immunomodulation therapy or immunotherapy has gain clinical traction in inhibiting checkpoints in pro-tumor pathways to increase sensitivity to chemotherapy.

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Tumor Associated Macrophages (TAMs)

Pro-Tumor Functions:

  • Direct secretion of angiogenic growth factors leading to increase in VEGF and MMPs

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anti-CCL2 (monocyte chemoattractant protein-1)

Control

Treated

CT26 cell

Monocyte

IL-1-β

TNFα

CCL2

CCR2

anti-CCL2

Blood vessel

anti-CCL2 has been linked to reduced tumor burden and recurrence risk in various cancers (i.e. breast and prostate). However, it has not been studied in CRC.

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Does the blockade of TAM recruitment via the CCL2 cascade increase tumor sensitivity to 5-FU and can the changes in tumor perfusion be quantified through diffuse reflectance spectroscopy (DRS) and immunohistochemistry (IHC)?

Research Question

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Subcutaneous Allografts

75 mm3

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Greening, G. et al Biomedical Optics Express (2018)

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Combination therapy shows a slowing trend in tumor volume and improves tumor volume limited survival in CT26 murine model.

Effect on Tumor Volume and Survivability

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DRS Perfusion Metrics

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Combination therapy shows improvement in oxygen saturation and oxygenated hemoglobin.

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DRS Perfusion Metrics

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Combination therapy shows some improvement in total hemoglobin, but not in deoxygenated hemoglobin.

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DRS Validation through IHC

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High CA-IX, Low StO2

Low CA-IX, High StO2

DRS can be a suitable, non-invasive optical tool that can monitor treatment response over time.

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TAM Quantification

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Control

anti-CCL2

anti-CCL2 has shown a significant reduction in TAMs over time.

**** p < 0.0001

*** p = 0.0001

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  • Combination therapy showed improvement in DRS perfusion metrics.

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  • anti-CCL2 therapy showed a significant reduction in macrophage recruitment over time.

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  • IHC validation showed that DRS can be suitable tool in monitoring treatment response.

Conclusions

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Translational Biophotonics and Imaging Laboratory

Dr. Timothy Muldoon

Kathryn Miller

Ariel Mundo

Ainsley Jackson

Sriya Pokharel

Lab Alumni

Dr. Gage Greening

Collaborators

Dr. Narasimhan Rajaram

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Acknowledgements

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Effects of Macrophage Targeted anti-CCL2 Immunotherapy on Functional Tumor Response

Shelby Bess

​

​

Department of Biomedical Engineering, University of Arkansas

TGIF: Graduate Seminar

October 9, 2020

​

​

​

​

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