Profile:
Dr. Robert Kralovics, PhD
Medical University of Vienna
Harnessing the Immune System: Dr. Robert Kralovics’ Groundbreaking MPN Research
Dr. Robert Kralovics is known for his relentless focus on unraveling the mysteries of myeloproliferative neoplasms (MPNs) —a family of rare blood cancers. As he admits, “I’ve been told I’m absent-minded because if someone suddenly talks to me, I’m just thinking about the research problem in the lab.”
This persistence and focus led Dr. Kralovics to make monumental discoveries in the field. His genetic research played a critical role in identifying two of the three major gene mutations behind MPNs: JAK2 and CALR. These groundbreaking findings set the stage for a new era of MPN research. Now, through the support of the MPN Research Foundation (MPNRF), Dr. Kralovics aims to use the immune system to target malignant cells.
The body’s defense against cancer
The human immune system works tirelessly to identify and destroy cancer cells. Tumor cells often display unique proteins, called neoantigens, on their surface that can be recognized by vigilant immune T-cells. As Dr. Kralovics explains, “It is one of the evolutionary advantages of humans and mammals in general that we have this immune surveillance.” However, in MPN patients, this natural defense system isn’t enough.
While it hasn’t captured the attention of the immune system, one protein, mutated calreticulin (mutCALR), is quite popular amongst MPN researchers. This neoantigen, which appears as an antenna on the surface of MPN cancer cells, should theoretically alert the immune system to an attack. Yet, in many patients, mutCALR escapes notice or only produces ineffective antibodies, allowing cancer to grow unchecked. The question driving Dr. Kralovics’ research is simple: Why?
A window into new therapies
The weak mutCALR antibodies produced by some MPN patients offer valuable insight. “Why don’t we just take those antibodies, reformat them, and see whether we can actually come up with a new immune therapy?” Dr. Kralovics proposes.
By isolating and studying the naturally occurring antibodies in MPN patients, Dr. Kralovics’ team aims to uncover new ways to target mutCALR, as well as explore other neoantigens that could broaden treatment options for patients. Working from this new antibody library, researchers can engineer highly effective therapeutic antibodies that grab the immune system’s attention, literally.
Targeting cancer with T-cell engagers
Dr. Kralovics’ research will utilize an exciting technology called bi-specific T-cell engagers (TCEs). “These are antibodies that basically establish an artificial connection of the cancer cell and the T cell,” Dr. Kralovics explains. Once the antibody has grabbed hold of a T cell with one arm and a cancer cell with another, the T cell is activated to attack and destroy the cancer cell they’ve become tethered to.
By designing TCEs to attach to reformatted neoantigens, the team hopes to engineer a treatment that can selectively kill MPN cancer cells without harming healthy tissue. Early laboratory tests will determine which antibodies show the most promise, and the most effective candidates will then move on to studies in animal models.
The promise of immunotherapy
Immune-based treatments offer advantages over other therapeutic approaches. By harnessing a patient’s own immune system Dr. Kralovics’ team aims to develop treatments that are more effective and less toxic than traditional drug therapies. “Developing a small molecule drug: it’s more expensive, it takes longer, there’s toxicity, there’s instability in some people… But by the nature of the immune system, it’s there! And it’s the most effective.”
Driven minds
Dr. Kralovics admits, “this focus, this constant persisting need for research just burnt me out a couple of times.” Consumed with a fascination with MPN research, he shares that “I just see a bone sample, that my student sends me a chart of the recent data, and I’m unusable for an hour.” Yet his dedication to one of the most challenging cancer fields has undeniably improved the lives of countless patients.
With support from MPNRF, Dr. Kralovics’ current project could pave the way for a new class of treatments for MPN patients, turning their immune system into a weapon against the disease. By focusing on mutCALR and other neoantigens, the project has the potential to revolutionize how MPNs are treated—offering patients new hope for life-saving therapies.
