Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.
Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.
The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.
Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.
Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.
With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.
The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.
Dendritic cells proved more potent than macrophages at priming CD8+ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”
The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.
The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).
When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.
In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.
But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.
When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.
And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.
The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.
“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”
