Nurturing a diet rich in PTCL

In this issue of Blood, Jain et al demonstrated that successful therapeutic targeting of the CD47-signal regulatory protein α (SIRPα) axis in peripheral T-cell lymphoma (PTCL) was highly dependent on the Fc-FcγR interaction and was augmented by cotreatment with the anti-CCR4 targeted mogamulizumab.¹ 

It has been nearly 120 years since the famed German physician-scientist Paul Ehrlich coined the term “magic bullet”: the notion that one could create a therapeutic that directly targeted a disease-causing entity. Unbeknownst to most, however, Ehrlich spent the early part of his career researching how aniline dyes could help visualize new details in organs, tissues, and cells—research that would give him a distinctly different view of the cellular milieu. These insights would position him to appreciate the complex interactions mediated by an immune response. In 1908, Ehrlich shared the Nobel Prize in Physiology or Medicine with Élie Metchnikoff for their independent contributions to our early understanding of the immune system: Ehrlich for his work on chemical theory as a means of explaining antibodies and antitoxins, and Metchnikoff for his research on the role of phagocytes in destroying bacteria. At that point in time, these 2 remarkable scientists converged in Stockholm and helped establish time-honored principles. Now, more than a century later, Jain et al reveal how the contributions of Ehrlich and Metchnikoff have become intertwined yet again.

The complex mechanisms invoked by vastly different immunotherapies now rival what the chemotherapists have exploited for more than 90 years. From Ehrlich’s early vision of a magic bullet to virally engineered T cells, the plethora of immunologically directed cancer therapeutics has become daunting. The US Food and Drug Administration has now approved nearly 25 different monoclonal antibodies (mAbs) for the treatment of cancer, including drugs that have favorably changed the natural history of every B-cell malignancy. Conjugation of mAbs with cytotoxic “warheads” can produce an astounding diversity of antibody drug conjugates (ADCs), of which 4 are now approved for treating cancer in the United States, and well over 150 more are in active development. Brentuximab vedotin, a CD30-targeted ADC, is approved for systemic anaplastic large T-cell lymphoma, a disease defined by abundant CD30 expression. Immune checkpoint inhibitors (ICI) that block programmed cell death protein 1/programmed death-ligand 1, relieving the brakes on T cells, now have 7 commercial products. Chimeric antigen receptor (CAR) engineered T cells, which re-educate host T cells to target specific antigens and destroy tumor cells, have 2 products now approved for diffuse large B-cell lymphoma and acute lymphoblastic leukemia (ALL). T-cell– and natural killer–cell engagers seek to overcome the stochastically driven interactions between immune effector and target cells. One of those, a T-cell engager, has been approved for B-cell ALL. Most of the approved therapies have relied on redirection of the acquired immune system (CAR T cells, bispecifics, vaccines, ICI), or invoked principles of passive immunity (mAbs, ADCs). In the study by Jain et al, we learn of yet another new and promising immunologic approach, one predicated on enlisting the aid of the innate immune system.

Macrophages play 2 major roles in mediating immune response. First, they phagocytize bacteria and cancer cells, digesting the engulfed material into their component parts. The second and equally important role involves the processing of ingested components, eventually presenting them on their surface where they can be detected by antigen-specific T cells. Macrophages regulate their interactions with other cells through SIRPα, which binds to CD47 on the surface of cancer cells, thus inhibiting phagocytosis. CD47 itself delivers a “do not eat me” signal that preempts its own macrophage-mediated ingestion. Not surprisingly, cancer cells have found a way to coopt this biology, too.

By using preclinical models representing many PTCL entities, Jain et al systematically evaluate a host of factors that influence the activity of CD47 targeted therapies. Across PTCL cell lines, they establish that expression of CD47 alone is necessary but suboptimal in inducing macrophage-mediated phagocytosis. CD47, although it is prognostic in acute myeloid leukemia and some B-cell lymphomas²  but not in PTCL, is heterogeneously expressed across PTCL cell lines. CD47 was more highly expressed across PTCL cell lines and primary tissue compared with normal CD3⁺ T lymphocytes, establishing a theoretical basis for a therapeutic index. In a survey of the clinically available CD47-targeted agents, Jain et al characterize the diversity of agents, which ranges from simple ligand-blocking mAbs binding to CD47 or SIRPα to engineered decoy receptors (TTI-621) and bispecific agents that disrupt the CD47-SIRPα axis. These agents have their own strengths and limitations. Most share an immunoglobulin G1 (IgG1) backbone, which is critical for activity, owing to the higher affinity of IgG1 to bind Fc receptors on macrophages and efficiently activate complement. Clinical data for anti-CD47–targeted drugs in PTCL are limited, but for TTI-621, there are robust data that have demonstrated marked responses in patients with cutaneous and PTCL via both intravenous and intralesional injections.^3,4 

By interrogating a host of factors historically demonstrated to influence the activity of macrophages, such as major histocompatibility class I,⁴  SLAMF7,⁵  and pyroglutamation,⁶  the authors demonstrate that the latter 2 factors were not as important in PTCL. In their experimental systems, recruitment of effector cells through engagement of the drug Fc-macrophage-FcγRs was most critical. Other critical factors related to the elaboration of specific cytokines following anti-CD47 engagement included murine monocyte chemotactic protein-3 (MCP-3) and interleukin-18 (IL-18).⁷  MCP-3 drives migration of monocytes into tissue, which leads to their differentiation into macrophages. IL-18 is a proinflammatory cytokine that induces MCP-1 through the PI3K/AKT and MEK/ERK1/2 pathways.⁸ 

Importantly, the authors also demonstrated that anti-CD47–directed therapy potently improved the activity of mogamulizumab, an anti-CCR4 IgG1 antibody approved for patients with adult T-cell leukemia or lymphoma. These types of fundamental observations lay the groundwork for future combination studies and provide an innovative strategy to target PTCL in a rational way.

As with any drug development pursuit, the devil is in the details. Jain et al have established some new principles regarding anti-CD47–based treatment and have challenged others. Their studies underscore the need for prodigious correlative studies as probably the best strategy to optimize these agents in PTCL. Quoting Paul Ehrlich himself, “The first rule of intelligent tinkering is to save all the parts.”