The chemotherapy drug cyclophosphamide combined with the immunotherapy motolimod enhances the immune system’s fight against tumors in mice with advanced and metastatic cancers, according to the study “Definitive activation of endogenous antitumor immunity by repetitive cycles of cyclophosphamide with interspersed Toll-like receptor agonists.”
“Cancers can remain inconspicuous in the body for months to years before causing major problems, leading the immune system to coexist rather than to attack cancers,” Mayo Clinic cancer immunotherapist Dr. Peter Cohen, said in press release about the study recently published in Oncotarget.
Cohen co-led the study with Mayo Clinic immunologist Sandra Gendler, PhD, and postdoctoral fellow Soraya Zorro Manrique, PhD.
“We tested Toll-like receptor (TLR) agonists – drugs that mimic invasive bacteria – as a strategy to trick the immune system into attacking cancer as if it were a life-threatening infection. Since chemotherapy can enhance immunotherapy, we also screened the pairing of TLR agonists with over 10 different chemotherapy agents,” Cohen said.
The Mayo Clinic researchers used mouse models of highly aggressive forms of breast cancer (known as 4T1), and pancreatic cancer (Panc02). They observed, when cyclophosphamide was administered in combination with the TLR agonist motolimod, advanced 4T1 and Panc02 cancers underwent significant regression within two treatment cycles. Mice showed no cancer recurrence when completing five additional cycles of consolidating treatment. When combining TLR agonist and cyclophosphamide, researchers also saw permanent cancer eradication.
Previous studies showed that even before treatment, cancer-bearing mice carried immune cells called T-lymphocytes that were capable of directing immune responses against the tumors – they just required weekly injections of motolimod and cyclophosphamide to become effective. Because the impact did not depend on direct injection into the tumor, the result suggests a therapeutic impact for primary tumors and widespread metastases. Additionally, the combination therapy activated other immune cells, called monocytes (a type of white blood cell), to fight the tumor.
“It appears very likely that each round of treatment stimulates the bone marrow to churn out freshly activated monocytes, which distribute throughout the body, spare normal cells, and find and kill cancer cells,” Gendler said.
The combination therapy was very well tolerated and less toxic when compared to each treatment given separately.
Research to learn more is ongoing. Investigators are pursuing an FDA-approved clinical trial to test if the combination treatment is translatable to human patients and can impact other cancers including the pancreas, breast, colorectal, and melanoma.