Gregory L. Beatty, MD, PhD
Gregory L. Beatty, MD, PhD, who focuses his research on understanding the role of innate immunity in gastrointestinal malignancies, believes that macrophages are key regulators of tumor biology.
He is an assistant professor of Medicine in the Perelman School of Medicine at the University of Pennsylvania and an attending physician in the university’s Health System. Beatty discussed CD47 as an anticancer target with OncLive
OncLive: How might CD47 serve as a therapeutic target in cancer?
: In cancer, CD47 is upregulated on malignant cells. Increased expression of CD47 is associated with a worse prognosis across several solid malignancies such as ovarian cancer and glioma, and across hematologic cancers such as non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia.
The majority of initial studies investigating CD47 as a target were conducted in xenograft models that lack a competent immune system (that is, absence of T, B and NK cells). From these studies, it was shown for several human cancer cell lines, that anti- CD47 antibodies could inhibit tumor outgrowth, a finding that has been attributed to macrophagedependent phagocytosis of tumor cells.
In addition, CD47-blocking antibodies have been shown to enhance antibody–dependent cellular phagocytosis such that combining anti- CD47 with other tumor-directed antibodies (eg, rituximab) can improve therapeutic outcomes in preclinical models.
More recently, CD47-blocking antibodies have been investigated in immunocompetent mouse models and have revealed the potential of CD47 blockade to also stimulate T cell-dependent antitumor immune responses through dendritic cell-dependent cross-priming of T cells. Delivery of chemotherapy just prior to dosing with anti-CD47 may enhance this T-cell–dependent antitumor effect. Thus, CD47 could be a target for enhancing macrophage-dependent tumor debulking and also for promoting dendritic cell-dependent induction of durable antitumor T-cell immunity.
What are the most significant challenges or limitations to targeting CD47?
CD47-SIRPa interactions are but one element regulating macrophage biology in cancer. Macrophage function is dependent on cues received from the surrounding microenvironment.
As such, macrophage biology is inherently pliable—a macrophage can take on either pro- or antitumor behaviors. Their ability to phagocytose and debulk tumors will also be dependent on their recruitment to tumors and receipt of appropriate activation signals that stimulate phagocytic potential.
In addition to disrupting “don’t eat me” signals, macrophages must detect sufficient “eat me” signals on target cells to engage in phagocytosis. In this regard, combining CD47 agonists with other cytotoxic therapies such as chemotherapy and other antibody-based strategies designed to induce antibody–dependent cellular cytotoxicity (ADCC) or antibody–dependent cellular phagocytosis (ADCP) may be critical to realizing the potential of CD47 as a target in cancer.
Disrupting CD47-SIRPa signaling within the tumor microenvironment will also be dependent on effective penetration of CD47 antibodies into the tumor bed. This may be compromised in fibrotic tumors and those cancers with poor vascularity, such as pancreatic cancer. Thus, sufficient antibody biodistribution into tumors will likely be critical to the potential of this strategy to enhance macrophage-dependent tumor debulking.
The upregulation of CD47 on tumor cells as they circulate in the blood stream could make anti-CD47 antibodies a novel approach to limiting metastatic spread. In this case, achieving dosing that allows for sustained unbound levels of antibody in the peripheral blood may be important for targeting malignant cells as they intravasate into the bloodstream.
Finally, preclinical models have suggested a role for CD47 in cross-priming of T cells. Disrupting this pathway in “immunologically cold” tumors may be a way to improve T-cell immunosurveillance.
However, additional signals that activate antigen-presenting cells (eg, CD40) or sustain T cell-dependent effects (eg, PD-1/PD-L1 antagonists) will likely be necessary in patients where additional resistance mechanisms have been engaged to limit productive cancer immunosurveillance.
Overall, CD47 as a target is exciting but likely just one piece of a complex puzzle defining immunological resistance in cancer. The early- phase study reported out by Forty Seven, Inc showing limited single-agent activity is to be expected. Most interesting will be how CD47 antagonists can be combined with cytotoxic therapies and other immunotherapies to improve clinical outcomes in patients with cancer.