Despite the long-lasting benefits seen in patients treated with immune checkpoint inhibitors, such antibody-based treatments often carry troubling side effect events due to the systemic activation of the immune system. Now researchers may have found a way of delivering such drugs locally that lowers these effects and their severity.
In the study, “Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer,” published in the European Journal of Immunology, investigators found that delivering a low-dose of a CTLA-4 antibody directly into a tumor is as effective as an intravenous injection into the bloodstream, and results in decreased activation of the immune system.
Importantly, the study shows that systemic administration of immune checkpoint inhibitors is not required to eliminate small metastases missed by imaging techniques, as the local treatment can activate tumor-killing immune cells that recognize and attack distant tumors that had not received the therapy.
“We found that the therapy that we tested in a model system of bladder cancer could stimulate the immune cells to find and attack the cancer cells, even if it was administered locally. These results are very promising since they indicate that it’s not necessary to activate the body’s whole immune system, but only the one that is relevant in the tumour. This way adverse events caused by the drug can be reduced,” Dr. Sara Mangsbo, with the Department of Immunology, Genetics and Pathology at Uppsala University, Sweden, said in a news release.
CTLA-4 inhibitors, such as Yervoy (ipilimumab), have shown promising results in a wide range of tumor types, including melanoma, lung cancer, and bladder cancer. But patients often experience immune-related effects that derive from auto-immune reactions — the patient’s immune cells start attacking healthy tissues.
Although these events can be managed if detected in early stages, some people in early clinical trials died from side effects like colitis and diarrhea, leading researchers to try to optimize anti-CTLA-4 therapy to reduce its systemic effects while maintaining its therapeutic efficacy.
The benefits of local administration of anti-CTLA-4 in solid tumors was recognized in a melanoma Phase 1/2 trial, but whether such administration could be used in bladder cancer was not known.
The researchers examined whether a lower dose of anti-CTLA-4 — compared to the dose used in systemic treatments — injected locally in bladder tumors in mice would still induce their regression.
Findings revealed that low-dose anti-CTLA-4 immunotherapy had similar efficacy against the growing bladder cancer, while reducing the levels of circulating antibodies. Importantly, local administration of anti-CTLA-4 not only stimulated the immune cells to recognize and destroy other tumor masses that had not been treated with the drug, it also created memory T-cells that prevented tumors from growing when the treated mice were re-challenged with tumor cells.
Studies have suggested that bladder cancer patients with low PD-L1 levels might benefit from combination treatment, and several clinical trials testing anti-CTLA-4 drugs, like Yervoy, in combination with anti-PD-1 therapies, like Opdivo (nivolumab) or durvalumab, are currently ongoing.
For this reason, the researchers also tested whether low-dose anti-CTLA-4 could be combined with local low-dose or systemic high-dose anti-PD-1 drugs. Their results showed that the combination of anti-CTLA-4 and anti-PD-1 (either local or systemic) had stronger anti-tumor effects that either drug alone, improving long-term survival in treated mice.
“Although the murine model is not susceptible to toxicity induced by check-point inhibitors, these data serve as a proof-of-principle that PD-1 blockade may be complemented with local anti-CTLA-4 therapy and warrants further study in the clinical setting to assess side effects compared to systemic administration,” the investigators wrote.