1068P - Fasting mimicking diet reduces anti-OX40/anti PD-L1 and anti-PD-1/anti-CTLA-4 cardiovascular side effects in melanoma and lung cancer models

Background

Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are investegated in clinical trial to assess their benefits in prolonging overall survival in cancer patients. However, ICIs-induced side effects ranging from autoimmune endocrine disorders to mucositis and to a rare but clinically significant cardiotoxicity with high rate of mortality represent important limitations. Cardiovascular complications in ICIs-treated patients includes myocarditis, vasculitis, arrhythmia, fibrosis and heart failure. Moreover, both the limited efficacy in a large portion of patients and the acquisition of resistance represent additional limitations for ICIs, underlining the need for new immunotherapy strategies. Fasting mimicking diets (FMDs) applied for several days periodically are emerging as highly promising enhancers of a wide variety of cancer therapies including immunotherapy.

Methods

A preclinical study in melanoma and lung tumor-bearing mice treated with two combinatorial ICIs therapies (anti-OX-40/PDL-1 or antiCTLA-4/anti-PD-1) during a standard or FMD was performed.

Results

FMD is highly effective in inhibiting the growth of melanoma, unlike anti-PD1/anti-CTLA4 and anti-OX40/anti-PD-L1 immunotherapy which are ineffective against both melanoma and lung cancer. However, FMD in combination with anti-OX40/anti-PD-L1 seems tofurther delay melanoma and lung cancer growth, although this trend is not statistically significant. On the other hand, cardiac fibrosis, necrosis and hypertrophy were reduced in the FMD vs standard diet group in both cancer models. Immune infiltration of CD3⁺ and CD8⁺ cells in myocardial tissues was reduced in FMD indicating myocarditis inhibition effects of the dietary intervention. Systemic and myocardial IL-1α, IL-1β, IL-6, IL17-α, G-CSF, and GM-CSF levels were also reduced in the FMD vs standard diet group.

Conclusions

These results indicate that FMD cycles applied to mouse models of melanoma and lung tumor reduce biomarkers involved in cardiovascular disease and resistance to immune-dependent activity without interfering with ICIs therapies.

Clinical trial identification

Legal entity responsible for the study

Longevity Institute and Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.

Funding

Ministero della Salute.

Disclosure

All authors have declared no conflicts of interest.