Understanding 4 classes of cutting-edge biologic agents

Biologic agents or “biologics” may seem new, but you might be surprised to learn that the first biologic was approved nearly four decades ago—in 1982. That biologic was recombinant human insulin, and since it came to market, biologics have become one of the fastest-growing segments of the US pharmaceutical market.

Biologics encompass a gamut of products including vaccines, blood/blood components, gene therapy, allergenics, somatic cells, and recombinant therapeutic proteins. They can consist of sugars, proteins, or nucleic acids, as well as living cells and tissues. Biologics are derived from human, animal, or microorganism sources, and can be produced via biotechnology.

According to the FDA, “Biological products often represent the cutting-edge of biomedical research and, in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have no other treatments available.”^[]

Because biologics are complex therapies used to treat a wide variety of conditions (and patients), physicians should pay heed to them. Let’s look at four classes of biologic agents, which are used to treat cancer or inflammatory disease.

CAR-T cell therapy

Before the advent of biologics, cancer was treated with surgery, chemotherapy, and radiotherapy. The advent of immunotherapy changed all that.

One rapidly emerging immunotherapy strategy involves collecting and using patient immune cells to target cancer, which is referred to as adoptive cell transfer (ACT). To date, CAR T-cell therapy is the form of ACT that has advanced most rapidly in clinical trials.

CAR-T was originally limited to small clinical trials for patients with advanced blood cancers, however, the treatment has gained favor because of remarkable successes in certain patients for whom all other treatments had failed.

To date, three forms of CAR-T cell therapy have been approved by the FDA: tisagenlecleucel for acute lymphoblastic leukemia (ALL); axicabtagene ciloleucel for diffuse large B-cell lymphoma; and brexucabtagene, which is is the first FDA-approved CAR T-cell therapy for mantle cell lymphoma. The focus of treatment with CAR-T cell therapy has mostly centered on ALL—in particular, refractory pediatric ALL, where clinical successes have been groundbreaking.

“As its name implies, the backbone of CAR T-cell therapy is T cells, which are often called the workhorses of the immune system because of their critical role in orchestrating the immune response and killing cells infected by pathogens,” according to the National Cancer Institute.^[]

CAR T-cell therapy requires drawing blood from patients and separating out the T cells. Next, the T cells are genetically engineered, using a disarmed virus, to produce receptors on their surface called chimeric antigen receptors, or CARs.

Of note, with newer generations of CAR T cells, co-stimulatory domains have been added to enhance the production of T cells after infusion and enable prolonged survival of these T cells.

CAR T-cell therapy can result in serious adverse events, including cytokine release syndrome and B-cell aplasia, due to the immune effects of T cells. CAR T-cell therapies can also lead to cerebral edema and other neurotoxicities.

Immune-checkpoint inhibitors

Cancerous cells evade T-cell mediated cytotoxic damage via various mechanisms, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1)—and it’s the identification of these molecular mechanisms that ushered in the modern era of immunotherapy in cancer treatment.^[]

Agents that confound these mechanisms allow for the body to recover dysfunctional T cells and regress various types of cancer. In certain cancers like metastatic melanoma and non-small cell lung cancer, immunotherapy is first-line treatment.

According to the authors of an article published in Nature Reviews Clinical Oncology, “Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade.”^[]

Examples of PD-1 inhibitors include pembrolizumab, nivolumab, and cemiplimab. Examples of PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab. Ipilimumab is an example of a checkpoint inhibitor that targets CTLA-4.

ICIs are responsible for a highly specific category of complications referred to as immune-related adverse events (irAEs).

“Immune-related adverse events (irAEs) are a unique spectrum of side effects of ICIs that resemble autoimmune responses,” wrote the authors of a review in BMC Medicine.^[]

They added that irAEs affect nearly every organ of the body—mostly commonly the skin, gastrointestinal tract, lung, and endocrine, musculoskeletal, and other systems.

“Since irAEs occur via a process of immune activation, suggesting that the exhausted immune cells have been reinvigorated and attack not only tumor cells but also normal tissue, theoretically, the occurrence of irAEs may indicate a better response to ICI therapy. Nevertheless, whether irAE development is predictive of the ICI response remains controversial,” the authors wrote.

TNF inhibitors

In a high-powered retrospective study published in Pharmacologic Research & Perspectives, investigators examined utilization trends between January 2012 and March 2019 for biologic anti-inflammatory agents, using a large US healthcare claims database.^[]

The investigators noted 90,360 incident episodes of tumor necrosis factor-alpha inhibitors (TNFi), with adalimumab the most frequent TNFi drug, representing 47% of all TNFi episodes. Moreover, this drug demonstrated a steady rise in use during the study period vs other TNFi agents. Of note, other anti-TNF drugs approved for clinical use include infliximab, certolizumab pegol, golimumab, and etanercept.

Adalimumab is a subcutaneously administered disease-modifying antirheumatic drug (DMARD) used in the treatment of rheumatoid arthritis and other chronic debilitating diseases that are regulated by tumor necrosis factor. Adalimumab binds to tumor necrosis factor-alpha (TNF-alpha) 2, 3 and inhibits interaction with the p55 and p75 cell surface TNF receptors, as well as lysing surface tumor necrosis factor expressing cells in vitro while complement is present.

TNF is a cytokine that occurs naturally and contributes to inflammatory and immune response. Increased levels of TNF are present in the joint synovial fluid of patients' rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and contribute to inflammation and joint destruction.

Non-TNF inhibitors

In the aforementioned study from Pharmacologic Research & Perspectives, the most common non-TNFi agent used was rituximab, which represented 44% of 70,506 incident episodes of administration.

The non-TNF inhibitors rituximab, abatacept, and tocilizumab are commonly administered to patients who do not respond to anti-TNF agents. These drugs, however, have not been compared with each other by means of randomized controlled trials.

Rituximab is a monoclonal antibody that targets the CD20 antigen, which is located on the surface of normal and malignant B lymphocytes. After binding CD20, this agent mediates B-cell lysis, with possible mechanisms including complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

With regard to rheumatoid arthritis (RA), B cells likely are involved in disease pathogenesis, as well as chronic synovitis. Specifically, B cells may play a role in the production of rheumatoid factor and other autoantibodies, antigen presentation, T-cell activation, or the production of proinflammatory cytokines, which are all important components of autoimmunity and inflammation.

In addition to RA, rituximab is also used to treat non-Hodgkin lymphoma, chronic lymphocytic leukemia, and granulomatosis with polyangiitis (formerly Wegener’s granulomatosis).