In cancer research, blood cancers have always stood apart. The group, which includes leukemia, lymphoma and myeloma, corrupt various cells within the blood, lymph nodes and bone marrow. For patients, hematological malignancies, like their solid tumor counterparts, are diverse. Some are easy to treat; some are nearly impossible. Some move quickly; some exist for decades, unnoticed.
For researchers, blood cancers can be a broad target. Because such malignancies circulate throughout a patient’s system, they can be relatively easy to access and study. Drug delivery can be easier too. Blood cancers also tend to be less biologically complex than solid tumors, with fewer redundant pathways. That can speed and simplify assessments in clinical trials.
By dint of these factors, blood cancers have long served as a proving ground for new cancer treatments. Some of the first chemotherapy drugs were developed for a blood cancer, and bone-marrow transplants were driven by the field. The first breakout kinase inhibitor was approved in 2001 for a form of blood cancer, as was the first B-cell lymphoma (BCL) 2 inhibitor in 2016 and chimeric antigen receptor T (CAR-T) cell therapy in 2017.
The pattern holds today. Blood cancer researchers, particularly in the space of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), are exploring a host of new targets, mechanisms and potential therapeutic platforms, all of which could guide the development of new treatments.
“We’re talking about whole categories of treatment that did not exist 10 years ago, when we were only using chemotherapy,” says Mohamed Zaki, a hematological oncologist and the vice president and global head of oncology development at AbbVie. Great innovations have already arrived and are in the hands of treating physicians, but as more develop, says Zaki, they “might lead eventually to cure, rather than disease control or just treating the symptoms.”
A cascade of targets
In the past two decades, treatment options and ongoing research for hematological malignancies have grown beyond chemotherapy to include chemoimmunotherapy, CAR-T cell therapy and monoclonal antibodies, among others. Across them, one dominant theme is the development of targeted therapies. As scientists learn more about the molecular pathways that govern a specific cancer, they identify targets that could slow or stop its progression. In blood cancers and some solid tumors, two of the current therapeutic targets that have garnered much interest are the proteins BCL-2 and Bruton tyrosine kinase (BTK).
BTK plays a prominent role in B-cell signaling. When an antigen attaches to a B-cell receptor, it sets off a cascade of actions — some of which are modulated by BTK — that guide an immune response. BTK also drives interactions with other immune cells, including dendritic cells and macrophages, and plays a regulatory role in inflammation.
BCL-2 is the most prominent member of a family of proteins, which includes those that stimulate cell death (pro-apoptotic) and proteins that help cells survive (anti-apoptotic). Typically, anti-apoptotic BCL-2 proteins inhibit pro-apoptotic ones, and some semblance of balance is maintained.
In the cases of both BTK and BCL-2, problems start when that balance is lost. The overexpression of BTK and anti-apoptotic BCL-2 proteins are signatures of CLL and AML, and because of this, a few different inhibitors have been developed and approved to curb disease progression.
Research into the development continues. In one interesting effort, Zaki says that researchers at AbbVie recently determined the 3D structure of BCL-XL, a well-documented anti-apoptotic BCL-2 regulator. An understanding of that structure could define BCL-XL’s binding properties, which is the first step in inhibiting the molecule.
As with any translational research, the path may be uncertain but the destination is not.
“With specific therapies targeting BCL-2 and BTK proteins in the cancer cell, you put more of your force on the cancer, unlike chemo which targets all rapidly growing cells – both healthy and cancer cells,” Zaki says. While it is possible targeted inhibitors could affect healthy cells, overall results point to improved patient outcomes and reduced traditional toxicity seen with chemotherapy.
Strength in specificity
Monoclonal antibody (mAb) therapeutics have been a staple of cancer care since 1997, when the first one was approved by the U.S. Food and Drug Administration (FDA) to treat low-grade or follicular B-cell non-Hodgkin lymphoma, a blood cancer. Since then, dozens, if not hundreds, of cancer-indicated mAbs have reached the market.
Their strength is their specificity. Because mAbs bind very specifically to targets, clinicians can use them to modulate specific pathways. They can also combine mAbs with established therapies, improving the overall results.
While the shift toward combination therapies is universal across cancer care, a number of recent studies have examined combinations of BTK or BCL-2 inhibitors and mAbs. One team of scientists treated CLL patients with a BCL-2 inhibitor and an anti-cancer monoclonal antibody, which looked promising for some patients. Similarly, another group of scientists saw improvements in CLL patients from a combined treatment of a BTK inhibitor and a monoclonal antibody. A different team showed positive results when combining a BCL-2 inhibitor and a chemotherapeutic for patients with AML.
The development of antibody-drug conjugates, or ADCs, is another promising research area. These engineered therapeutics attach a chemical payload, such as a chemotherapy, to an antibody specific to a tumor. When the antibody binds to the tumor, it moves inside the cell and releases its toxic payload.
In theory, ADCs enable the use of fewer chemicals, which would in turn reduce side effects. But progress in developing them has until recently been slow. Early failures helped researchers improve ADCs — some carrying more toxin, others carrying a more lethal toxin, and some using antibodies that provide more specific targeting on the intended cells. Consequently, the FDA approved three ADC’s for cancer treatment in 2019, one of which was a treatment for blood cancer.
The next frontier of antibody design is represented by bispecific and trispecific antibodies. These engineered antibodies bind two or three sites, as opposed to just one. Most commonly, they serve to bring immune cells into close proximity with cancerous cells, heightening the body’s natural cancer-fighting capabilities. So far, only one bispecific antibody has been approved for treatment. Its indication is for children and adults with acute lymphoblastic leukemia (ALL).
A platform solution
Of all the trends in cancer research, the recent development of CAR-T cell and related cell therapies has generated the most attention. Since the emergence of the first FDA-approved CAR-T cell therapy, researchers have been piling into the field.
CAR-T cells are engineered to bind to a specific surface protein on a patient’s cancer cells. Once bound, a T cell’s natural cytotoxic activity dispatches the cancer cell. CAR-T cells are tailored to a patient’s cancer, which makes them highly targeted, but also expensive.
On the surface, emerging cell therapies could not seem more different than ADCs or small molecules. But the next generation of cancer treatments share a common quality: They are all highly targeted. That’s a strength, but, Zaki says, it could also be a weakness. Targeted therapeutics are only as good as the diagnostics that help doctors prescribe the right treatments and measure their effects.
A lot of work is ongoing in this domain, Zaki says and ultimately developments will need to run in parallel. “Using science to go after a cancer’s mechanism of action and creating a companion diagnostic is the future of treating hematologic malignancies,” he says.
Given the progress made in the last decade alone, that day is certainly approaching. In the meantime, blood cancer treatments, as they always have, will continue to rapidly advance.
To learn more about developments in blood cancer, visit AbbVie's oncology resource.
