Regional Therapies
Eran Nizri, MD, PhD
Head of Unit
Tel-Aviv Sourasky Medical Center
Jerusalem, Israel
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Recent evidence casted doubt on the efficacy of heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal metastases (PM) from colorectal cancer (CRC). HIPEC was previously shown to increase tumor immunogenicity due to lysis of tumor cells and the expression of novel antigens to the immune system. Our aim was to explore if this effect could be augmented by the addition of check-point inhibitor (CPI) in an experimental animal model.
Methods:
PM-CRC were induced in C57BL mice by i.p. injection of 1X106 MC38 cells. After 7 days and establishment of PM, mice underwent HIPEC with mitomycin C at human equivalent dose (0.01mg/ml) and treated by anti-PDL-1 antibody (100µg/kg X 4). Mice were followed up for survival and weight. Tumor tissue was obtained for analysis of immunological infiltrate in different time points.
Results:
: In vitro experiments with MC38 cells showed that treatment with mitomycin C in the same conditions as in HIPEC increased mRNA expression of (Heat Shock Proteins (HSP)-70 and 90 by 73 and 3.3 fold (p< 0.001, p< 0.05, respectively), both proteins known as immunogenic for dendritic cells. As expected, mice who underwent HIPEC had longer survival than those who did not (19.4±3.3 vs. 15±4.9 days, p< 0.05). Histological analysis showed increased CD8 and CD68 infiltration into omental and visceral metastases in HIPEC treated mice (12±1.2 vs. 8±2 cells/HPF, 14±0.8 vs. 10±0.5; 7±1.5 vs. 4±0.8, p< 0.01, respectively). Next, we treated mice with CPI before and after HIPEC. Mice treated by CPI had increased OS than those treated by HIPEC alone (23.67±3.18 vs. 19.4±3.3, p< 0.05). Immunological infiltrate analysis showed increased CD8 and CD68 infiltration as compared to mice treated by HIPEC alone.
Conclusions:
HIPEC increases immune cell infiltration into PM, transforming "cold" nodules into warm ones. The addition of CPI to HIPEC can augment anti-tumor immune response in PM. CPI should be considered as novel adjuvant to HIPEC.