Repurposing Heart Drugs Could Improve Responses to PDL1 Immunotherapy in Cancer Patients

Angiotensin receptor II blockers are often prescribed to control hypertension or for heart failure, kidney failure, or following a heart attack.

New preliminary study findings have found that angiotensin receptor II blockers (ARBs), a class of commonly used heart medications, may improve patient responses to programmed death-ligand 1 (PD-L1) immunotherapy.

ARBs are often prescribed to control hypertension or for heart failure, kidney failure, or following a heart attack. According to the study authors, they reduce the action of angiotensin II, which plays a role in narrowing blood vessels and increasing blood pressure. ARBs block the receptors that angiotensin II works on, which are found in the heart, blood vessels, and kidneys.

According to Julius Strauss, MD, co-director of the clinical trials group at the Laboratory of Tumor Immunology and Biology, evidence has shown that when angiotensin II binds to the AT1R receptors, it can increase levels of other proteins, VEGF and TGF beta, which have both been linked to cancer growth and immune resistance. Based on this overlap between angiotensin II and the TGF beta pathways, investigators theorized that ARBs could play a role in cancer treatments.

Investigators analyzed data from 597 patients being treated with anti-PD-L1 drugs across 20 clinical trials. Patients had more than 36 different cancers, including prostate, lung, colon, ovarian, bladder, and cervical cancers. According to a press release, many were already taking ARBs or angiotensin-converting enzyme (ACE) inhibitors for heart problems unrelated to cancer.

“We decided to look at all the medications our patients were taking to see if any common medication or class of drugs might increase the likelihood of responding to anti-PD-L1 treatment,” Strauss said in a press release. “After an initial review, ARBs seemed to be the most promising.”

Strauss compared 71 patients who were taking ARBs with their PD-L1 therapy with patients who were not taking ARBs. He also analyzed 82 patients who were receiving ACE inhibitors compared with patients who were not.

According to the data, patients who were receiving ARBs seemed to respond better and more often to anti-PD-L1 therapy than patients who were not taking ARBs. The team found ARBs were associated with a statistically significant increase in the objective response rate (ORR) and the complete response (CR) rate.

Among the patients taking ARBs, the ORR was cancer shrinkage of at least 30%, a goal which was reached by 34% of patients taking ARBs compared with 17% of patients not receiving the drug. Furthermore, the CR rate was 11% in this group, compared with 3% in those not taking ARBs.

However, there was no statistically significant improvement in ORR or CR rates among patients taking ACE inhibitors compared with those who were not taking them.

“The possible reason for the different effects seen with ARBs and ACE inhibitors might be that although angiotensin II increases levels of VEGF and TGF beta when it binds to the AT1R receptor, it can actually decrease levels of VEGF and TGF beta when it binds to another receptor: AT2R,” Strauss explained. “Therefore, ARBs which selectively block just AT1R potentially work better at lowering VEGF and TGF beta levels than ACE inhibitors, which block both AT1R and AT2R.”

Strauss noted, however, that the findings are very preliminary and more trials are needed to evaluate whether ARBs are beneficial to patients with cancer. It would also be important to determine which cancer types may benefit the most, especially with anti-PD-L1 therapy.

REFERENCE

Existing heart drugs may help cancer patients respond better to PD(L)1 immunotherapy [news release]. EurekAlert; October 21, 2020. https://www.eurekalert.org/pub_releases/2020-10/eofr-ehd102020.php. Accessed October 27, 2020.