A team of researchers at the University of Texas MD Anderson Cancer Center launched a study with a simple question: Could commonly used medicines affect how cancer patients respond to drugs that boost the immune system’s ability to attack cancer? They analyzed the records of MD Anderson patients who were treated with immune checkpoint inhibitors like Merck’s Keytruda and Bristol Myers Squibb’s Opdivo.
The team made a surprising discovery: Patients with melanoma or lung cancer who were taking antihistamines and checkpoint inhibitors at the same time had significantly better outcomes than did patients who did not take the allergy drugs. They reported the discovery in the journal Cancer Cell.
Specifically, it was antihistamines targeting histamine receptor H1 (HRH1) that seemed to correlate with positive responses to checkpoint inhibitors, the MD Anderson team found. That led them to consult the Cancer Genome Atlas and other cancer databanks to see whether they could determine the exact role HRH1 plays in checkpoint inhibition.
Turns out high levels of the histamine receptor in tumors are related to malfunctioning T cells, which are the immune cells that are vital to launching an effective immune response to cancer. High expression of HRH1 also correlated with a lack of response to checkpoint-inhibiting drugs and poor survival, the researchers reported.
The researchers went on to discover that both HRH1 and histamine appeared at high levels in the tumor microenvironment—but they came from different places. They didn’t find HRH1 in cancer cells, but they found plenty of it in tumor-associated macrophages, which are cells in the tumor microenvironment that suppress the immune response.
Histamine, on the other hand, was overexpressed in cancer cell lines as well as in tumor samples from patients.
The MD Anderson researchers blocked HRH1 in macrophages either by genetically modifying the cells or by treating them with antihistamines. Both methods crippled the macrophages’ immune-suppressing actions, which in turn amped up the activation of T cells and slowed tumor growth, they reported.
A combination of antihistamines and checkpoint blockade in preclinical models of breast cancer and melanoma prolonged survival over checkpoint blockers alone, they added. They also tried combining antihistamines with antibodies that block VISTA, which stands for V-type immunoglobulin domain-containing suppressor of T-cell activation—a receptor that’s known to suppress T cells and that seemed to be inhibited by antihistamines. That combination also worked well, they reported.
The VISTA discovery was notable given that it is already a hot target in oncology. Last year, a Dartmouth College team reported that when T cells express high levels of VISTA, they limit the activation of new T cells, which in turn inhibits the immune response to cancer. Anti-VISTA antibodies are currently in clinical testing, the MD Anderson researchers noted.
The researchers believe using antihistamines in cancer patients who have high levels of histamines in their blood could be a viable strategy for enhancing immunotherapy approaches. They are now designing clinical trials to test combination treatments.
“There is more work to be done, but we are excited to continue exploring possible therapeutic applications with antihistamines, which offer an inexpensive approach with minimal side effects,” said co-author Dihua Yu, M.D., Ph.D., interim chair of molecular and cellular oncology at MD Anderson, in a statement.