As physicians, we aim to prevent or cure our patients’ ailments every day. On rare occasions, we are able to accomplish this by discovering a breakthrough. Our John Theurer Cancer Center clinical investigators recently presented their breakthrough at the American Association for Cancer Research (AACR) annual meeting. The result of their clinical trial opens an entirely new field of cancer research by utilizing a patient’s own immune system to significantly improve their survival outcomes in advanced melanoma and, potentially, many other tumor types.
Kudos to the entire team. For more on their research and what this could mean for our patients and many more around the world, lead investigator Andrew Pecora, M.D., FACP, CPE, co-Division chief of the JTCC skin and sarcoma division, breaks down their findings.
Daniel W. Varga, M.D.
Chief Physician Executive
President, Physician Services
John Theurer Cancer Center Participates in Breakthrough Immunotherapy Research in Melanoma
By: Andrew L. Pecora, M.D., FACP, CPE
John Theurer Cancer Center
Our John Theurer Cancer Center clinical investigators participated in the phase 2b mRNA vaccine immunotherapy melanoma trial as members of our NCI designated Georgetown Lombardi Comprehensive Cancer Center consortium.
The breakthrough technology is centered on using melanoma cells taken from the patient to manufacture (patient-tumor specific) messenger RNA (mRNA-4157/V940) to educate and stimulate that patient’s T cells to better identify and kill their cancer cells. In the trial, patients with stage III and IV melanoma rendered disease free by surgery, who were randomized to receive a combination of mRNA-4147/V940 and a checkpoint inhibitor, pembrolizumab experienced a significantly lower recurrence rate (22.4%) versus the group randomized to receive pembrolizumab alone (40%) at two years of follow-up.
Our physicians and research staff at John Theurer Cancer Center (JTCC) are international thought leaders in the field of immunotherapy, having led many scientific and clinical breakthroughs over the past 25 years in blood and marrow stem cell transplantation, antibody-based therapeutics and newer cellular medicines including CAR T cells. The use of mRNA technology to educate and stimulate a patient’s immune system to fight and cure cancer is the next important chapter in the field of immunotherapy. So how does mRNA technology work and why is this such a big deal for the field of immunotherapy and our patients?
The History of Immunotherapy
Historically, in writings from ancient Egypt, it was first recognized that cancer (tumors) would occasionally spontaneously disappear in people after experiencing a high fever presumed to be caused by an infection. However, it was not until the 1800s that two German scientists (F. Fehleisen and W. Busch) were acknowledged for documenting tumor regressions after a bacterial (erysipelas) infection. Later that century, William Coley - the credited father of immunotherapy - began injecting a variety of bacteria (Coley’s toxin – commercialized in 1899) into different tumor types and recorded responses opening the field of immunotherapy. Immunotherapy next advanced with the discovery of interferons in 1945 in Nutley, NJ (the current site of the Hackensack Meridian Health Center for Discovery and Innovation) and was followed, in 1967, by the discovery that a patient’s T cells could recognize and kill their cancer cells.
This was followed by learning that a bacterium, BCG, could be used to successfully stimulate patients' T cells to recognize and kill the bladder cancer. The knowledge of how T cells were educated to recognize cancer cells as foreign and something to be killed by our immune systems resulted from the discovery and description of dendritic (antigen presenting) cells in 1973 by Dr. Ralph Steinman of The Rockefeller University. In the 1980s a variety of immunotherapy antibodies were produced using recombinant DNA technology and directed at cancer specific proteins (mutated HER2) as well as normal proteins (CD-20) expressed on the surface of cancer cells. JTCC physicians took part in most of the antibody clinical trials conducted through the 1990’s where immunotherapy antibodies resulted in significant improvements in survival resulting in numerous FDA approvals.
Immunotherapy took the next major step forward resulting in the award of Nobel Prizes, with the discovery and then commercialization of check-point inhibitors (2011). JTCC physicians took part in the development of the first check-point inhibitor FDA approved, ipilimumab (2011) and has continued to participate in clinical trials that has brought to market a variety of other checkpoint inhibitors and more recently CAR T cells for the treatment of a broad array of cancer types. Today, checkpoint inhibitor-based immunotherapy has changed the previously expected limited survival for most of the common solid tumors, offering long term survival and in some, cures. Pembrolizumab, a check-point inhibitor, was co-administered in our study with mRNA 4157/V940.
Immunotherapy’s Next Chapter
Immunotherapy research is now entering its next chapter by addressing why checkpoint inhibitors are not universally effective. The effort is being led by the breakthrough in mRNA-based tumor-patient specific vaccines. To understand the current limitations of immunotherapy, we need to consider how our immune systems recognize cancer to kill it. It all starts with our DNA that resides in every nucleated cell in our bodies (50% from mom and 50% from dad). DNA codes for the production of proteins that drive normal cellular function and our day to day lives. The reader of DNA to translate the code we inherited is called messenger RNA (mRNA). mRNA reads a segment of DNA code in our cell’s nucleus and then travels to the cytoplasm where mRNA translation produces proteins. In cancer the DNA code is altered, or mutated, from what we inherited and so the proteins produced are not normal and different in structure from what our bodies and our immune systems expect. These cancer proteins (neoantigens) are what cause the cells of our body to transform from normal to cells capable of growing uncontrollably (cancer) and taking our lives.
If educated to be recognized by our immune system, our T cells can search for, identify, and kill these cancer cells expressing neoantigens (immune surveillance) before they can take root and grow. However in patients with established cancer, our immune systems were not activated (educated) sufficiently, if at all, or once activated turned off by checkpoints expressed by the cancer cells (i.e. PD-L1). In blocking checkpoints with check-point inhibitors, the T cells activated to recognize and kill cancer cells expressing neoantigens can continue to do so and result in long-term remissions and, sometimes, cures. For T cells to do this they must first be educated to recognize the cancer proteins (neoantigens) and this is where the mRNA story begins. About half of the time T cells do not recognize the neoantigens because they are not presented properly or sufficiently by antigen presenting cells for T cell activation (education). As neoantigens are produced in the cancer cells, small pieces are broken off and combined with HLA-molecules. They are then brought to the cell surface of antigen presenting cells to activate T cells. Not all neoantigens produced will fit in the HLA molecules we have so they are not presented to T cells. Thus, the more neoantigens produced by a cancer cell (tumor mutational burden or TMB) the more likely some will fit in an HLA molecule pocket, and be presented to be recognized by and activate a T cell.
mRNA 4157/V940 Technology
The mRNA 4157/V940 technology significantly increases the likelihood of neoantigen presentation and recognition by T cells which improves T cell education and activation, resulting in better clinical outcomes as seen in this new trial. The mRNA technology starts with comparing a patient’s normal DNA sequence from collected healthy cells to the abnormal (mutated) sequence in collected cancer cells. Once the abnormal DNA segments are characterized, mRNA is manufactured from these abnormal (mutated) segments to then be injected into the arm of the patient like a vaccine. The injected mRNA is encapsulated by a fat globule and is taken up by lymph nodes throughout the body and enters antigen presenting cells residing in lymph nodes to produce patient tumor specific neoantigens likely to fit in the HLA-molecules of those antigen presenting cells. This process results in the vaccine effect of educating and stimulating T cells to kill cancer cells expressing these neoantigens. Neoantigens differ from patient to patient so by using the patient’s tumor to create a vaccine, the mRNA produced enables the patient’s antigen presenting cells to produce and present up to 34 neoantigens being expressed by that specific patient’s tumor.
In the trial presented at AACR that JTCC participated in, patients received a check-point inhibitor (pembrolizumab) every three weeks for up to 18 months and in those randomized to the mRNA vaccine, they received nine intramuscular injections every three weeks. By enabling the patient’s T cells to recognize their specific tumor neoantigens, it allowed their T cells to better identify and kill their cancer, resulting in the better outcome observed in the trial (versus checkpoint inhibitor therapy alone).
Improvements in mRNA cancer vaccine development is underway and this approach is now being tested across a broad array of cancer types responsive to checkpoint inhibitors. Immunotherapy has come a long way from ancient Egypt and in our lifetimes will likely advance much further not only to effectively treat and cure most cancers but ultimately prevent them from ever occurring. Our physicians, nurses, pharmacist, and research teams at JTCC will continue to lead the way in immunotherapy research and care.