PII-008 - FC RECEPTOR MODULATION AND POTENTIAL IMPACT ON CLEARANCE OF IMMUNE CHECKPOINT INHIBITORS IN CANCER CACHEXIA.

B. Remaily¹, T. Vu¹, J. Thomas¹, K. Kim¹, Z. Xie¹, Y. Guo¹, T. Costa¹, M. Manna¹, R. Britt¹, D. Owen², S. Kulp¹, T. Mace¹, L. Ganesan¹, C. Coss¹, M. Phelps¹; ¹The Ohio State University, Columbus, OH, USA, ²The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA.

Background: Cancer associated cachexia is a multifactorial syndrome characterized by irreversible loss of skeletal muscle and adipose tissue as a result of increased catabolism, energy expenditure, and increased metabolic activity[1]. In clinical populations, patients with cancer cachexia have elevated immune checkpoint inhibitor (ICI) catabolic clearance (CL), and this increased ICI CL serves as a prognostic indicator of overall survival, independent of dose and drug exposure[2]. This effect of increased ICI CL can also be illustrated in the murine Lewis Lung Carcinoma (LLC) model of cancer cachexia but is absent in the non-cachectic MC38 colon adenocarcinoma model [3]. Elevated ICI CL is independent of mAb variable region and target binding, suggesting an important role for the Fc constant region and Fc domain binding to Fc receptors (FcRs). We sought to understand changes in circulating leukocyte and FcR expression in multiple tumor models as to inform cachexia associated changes in FcR expression that could affect mAb PK.

Methods: Splenocytes from healthy C57BL/6 mice and C57BL/6 mice with LLC, and MC38 tumors were stained for mass cytometry analysis in order to measure FcR expression on 9 distinct leukocyte subpopulations.

Results: We found significant changes in immune cell populations and in expression of FcRn and FcRs in some immune cell subsets. Tumor models of cachexia that display increased clearance illustrate the general trend of increased FcRn expression, increased expression of activating (I,III, and IV) FcRs, and decreased expression of the inhibitory FcRIIb compared to non-cachectic, and tumor free controls.

Conclusion: These findings illustrate that FcR expression can change as a function of disease state, and that these disease state mediated changes have the potential to alter PK of ICIs and other mAb therapies.

1. Baracos, V.E., Martin L, Korc M, Guttridge D.C., Fearon K.C.H., Cancer-associated cachexia. Nat. Rev. Dis. Primers, 2018. 4: p. 17105.
2. Turner, D.C., et al., Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Clin. Cancer. Res., 2018. 24(23): p. 5841-5849.
3. Castillo, A.M.M., et al., Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans. JCSM Rapid Commun., 2021. 4(2): p. 232-244.