Immunotherapy has reshaped the cancer treatment landscape. This type of treatment boosts the immune system to fight cancer. However, for people with advanced brain cancer, immunotherapy options remain slim. Here, our Curious Dr. George asks Cancer Commons Scientist Matt Warner, PhD, about the challenges and future potential of immunotherapy for brain cancer.

Curious Dr. George: An accomplished molecular oncologist, you have now helped many brain cancer patients consider their options, both on your own and as part of virtual tumor boards. Immunotherapy has successfully revolutionized the treatment of many potentially lethal cancers. Why has the use of immunotherapy for brain malignancies seemed to lag?

Matt Warner, PhD: There are several reasons why cancers of the central nervous system (CNS) have been more challenging than other cancers to treat with immunotherapies. Despite recent studies demonstrating that the CNS is not as “immune privileged” as we once believed, it is still clear that 1) the unique anatomy of the brain and spinal cord, 2) the role of the blood-brain barrier at controlling which substances and immune cell subtypes can access the CNS, and 3) the limited presence of the lymphatic system within the CNS all decrease the ability of the immune system to patrol and attack cancers within the CNS versus other organs of the body.

Furthermore, CNS cancers often display fewer mutations in comparison to other cancers and therefore lack the immunogenicity to help the immune system identify and distinguish the cancer from the healthy neuronal tissue.

Lastly, as with all other cancers, you then have to compete with the immunosuppressive tumor microenvironment and the knowledge that chronic and excessive neuroinflammation as a result of hyperactivation of the immune system could also be detrimental to a patient. This presents concerns from a quality-of-life standpoint due to the impact of inflammation and swelling on the function of healthy neuronal tissue. It also poses disease management concerns because the immune system’s response to CNS cancer may also impact the survival, proliferation and invasiveness of gliomas.

CNS cancers therefore present some unique challenges for the immunotherapy-based treatments we currently have available in the clinic, highlighting why the clinical development of immunotherapies for these cancers has been less successful.

Despite these setbacks, I still believe immunotherapies will play a significant role in treating CNS cancers in the future. However, in order to be successful, this approach will most likely require novel combinations of immunotherapy-based treatments (for example, immune checkpoint inhibitors, dendritic cell and peptide-based anti-cancer vaccines, oncolytic viral therapies, and cellular therapy) with radiation, chemotherapies, targeted therapies, and/or Optune. Such combinations will no doubt help us move beyond the prior failings of immunotherapies being investigated as single agents, which lack the necessary activity to single-handedly enhance the immune system and treat cancers within the CNS.

Recent research findings provide some hope in this regard. For example, interim analyses from ongoing clinical studies and retrospective analyses from closed trials that investigated immune checkpoint inhibitors in glioma patients demonstrate that these drugs may need to be used around the time that patients are receiving their surgery, radiation therapy, or Optune treatment, and they may need to be targeted to patients with unique tumor mutational profiles. Additionally, more trials are now exploring combinations of immunotherapies and pharmacological agents to (hopefully) modulate the tumor microenvironment and make it more amenable to immunotherapy-based treatments.

Given how little we still understand about the brain and the activity of the immune system within the CNS, I am confident that we will one day celebrate the successes of immunotherapies in the treatment of CNS cancer patients.

Matt can be reached at matt.warner@cancercommons.org.

Cancer is so often a disease of older people that a whole medical field, “oncogeriatrics,” exists to address the topic. Deeper understanding of the links between cancer and aging could lead to better treatments. Here, our Curious Dr. George asks Cancer Commons Clinical Scientist Kaumudi Bhawe, PhD, about the relationship between cancer and aging processes that occur in individual cells in our bodies—throughout our lives.

Curious Dr. George: As a molecular biologist, you have worked with many forms and elements of cancer cells. Are there any similarities between the processes of cellular aging and the development of cancer?

Dr. Bhawe: Cancer is a disease of aging. According to the National Cancer Institute (NCI), cancer incidence increases dramatically after age 50, with the median age of people diagnosed with cancer in the United States being 66. While chronological age is definitely a cause of cellular aging, it is not the only cause. In fact, the process of cellular aging is known to happen in cells right from the time a human embryo is still developing. What then, exactly, is cellular aging, and what does it have to do with cancer? This is a timely question with the recent publication of a paper in the scientific journal Cancer Discovery entitled “Hallmarks of Cancer: New Dimensions.” This article highlights aging—or “senescent”—cells as one of the newly acknowledged enabling characteristics of all cancers.

Aging cells can be defined by accumulated damage to the macromolecules, such as DNA and proteins, that are important for the cells to maintain themselves, to grow, and to divide. Certain molecules in a cell, are involved in a mechanism that surveys and repairs DNA damage each time the cell undergoes division. If there is more damage than can be repaired, an aging cell either dies or cannot divide, and goes into what is called irreversible cell-cycle arrest. The above-mentioned mechanism ensures that cells with faulty macromolecules are not increasing in number, and in this sense, it is a disease-preventing mechanism. For a very detailed overview of the DNA-damage-response mechanism and its relevance to cancer, you can read this scientific review article that was published last year.

However, once an aging cell enters irreversible cell-cycle arrest, it can stay alive for quite some time; up to months, as demonstrated by lab-based research. Not only can it stay alive, it can also evolve based on the cues it is receiving from its environment, and importantly, it can alter the very environment it finds itself in. It has been discovered that such senescent cells have an abnormal metabolism and secrete hundreds of different signaling molecules including proteins and lipids. Readers interested in learning more about this exciting field of study can start with this article from the scientific journal Communications Biology and this video from the news site Technology Networks.

Some of the ways in which cells can be induced to undergo aging/senescence include the slow natural aging caused by going through multiple cell-cycles, leading to telomere shortening, exposure to toxic chemicals (including chemotherapy) and radiation, exposure to reactive oxygen species (ROS), and activation of cancer-causing genes (oncogenes). So, you can see that as a cancerous tumor is forming, or even during treatment, senescence mechanisms are at work in at least some of the cancer cells as well as some of the non-cancerous surrounding (stromal) cells, such as fibroblasts, blood-vessel-forming cells, and immune cells.

Three key common features shared between aging cells and cancer-developing cells are:

1) accumulation of DNA defects

2) altered metabolic activity, and

3) an increase in secretion of environment-modulating molecules.

The current challenge lies in discovering and cataloging the specific details of each of these three features in order to identify true molecular similarities, differences, antagonism, and cooperation between the processes of aging and cancer. The NCI funds initiatives for cancer and aging research at premier institutes across the U.S. in the hopes of addressing this challenge and developing new, better strategies for cancer prevention and treatment.

Dr. Bhawe can be reached at kaumudi.bhawe@cancercommons.org.

For people with advanced cancer, making sense of the complexities of cancer treatment can be truly daunting. Enter the oncology nurse navigator (ONN), a nurse with specialized training to help patients overcome any barriers they may face in accessing high-quality cancer care. At Cancer Commons, our Director of Patient Services Deb Christensen, MSN, APRN, AOCNS, OCN, applies her ONN training to ensure that every patient receives the guidance they need. Here, our Curious Dr. George asks her about her work.

Curious Dr. George: You are in charge of patient services at Cancer Commons. How would you describe how you use your ONN skills every day to assist patients with advanced cancer who seek help at Cancer Commons?

Deb Christensen, MSN, APRN, AOCNS, OCN: My first real exposure to oncology was as a nurse navigator in a large healthcare organization. Care coordination is one of the main roles of the ONN. Networking and forming partnerships with other departments and physician offices was key to successfully helping people navigate the complex landscape of oncology care. I had the opportunity to participate on a committee of nurses who updated the Oncology Nursing Association Nurse Navigator Competencies in 2017 and was coeditor of Oncology Nurse Navigation: Delivering Patient-Centered Care Across the Continuum (second edition).

These experiences allowed me to share my passion for the role of the ONN and grow in the profession. After working as an ONN, and then serving as the system lead for the navigation program, I retired from the organization and joined Cancer Commons as a nurse navigator.

I am peoples’ first point of contact at Cancer Commons. I assist people through the registration process and then contact them to learn more about their cancer history and assess their needs, goals, and expectations. An essential ONN skill that I use consistently is the ability to communicate in a way people can understand and follow. Our patient navigation specialist, Lauren Levine, and I assist the patients and their families with retrieving medical records, collaborating with our Scientists, and checking in at key points in the cancer journey. Our goal is to make the entire process personalized and as simple as possible. The entire Cancer Commons team collaborates to help clients create a plan to discuss with their local oncology team. This action plan is complimentary, informed by the latest scientific research, and curated by PhD scientists.

My new role as Director of Patient Services evolved out of the Cancer Commons team’s desire to provide a more personalized experience to clients and offer new services. Our team helps clients understand their treatment options and take potential next steps. Additional services being implemented include a Cancer Commons Plus subscription for ongoing follow up and communication with the science team, clinical trial enrollment assistance, and other assistance offered by the hour. The ability to put clients first by providing non-biased treatment options and timely compassionate care is at the heart of everything we do at Cancer Commons.

Deb can be reached at deb.christensen@cancercommons.org.

The existing drug development system “has failed miserably” for people with glioblastoma brain tumors, according to Al Musella, DPM, President of the Musella Foundation for Brain Tumor Research & Information, Inc. In partnership with Cancer Commons, his organization’s Brain Tumor Virtual Trial aims to speed discovery of promising new glioblastoma treatments.

Curious Dr. George: How might your Virtual Trial approach speed the process toward either validating or invalidating potential therapies for glioblastoma?

Al Musella, DPM: I have watched how the current drug development system works since 1992, and think we could do much better. There are many problems but the top ones, as they relate to malignant brain tumors, are:

1. The current system is set up to try to find one magic bullet that will successfully treat the disease. This concept has worked reasonably well for some diseases, but for brain tumors it has failed miserably. I feel that the ultimate cure for brain tumors will be a combination approach, and under the current system, it is very difficult to get the individual components of that ultimate cocktail approved by the U.S. Food and Drug administration (FDA).
2. There are not enough patients for the number of trials needed. About 10% of adult glioblastoma patients—about 2,000 per year—enter clinical trials. There are currently 318 glioblastoma trials open for enrollment, which means only six patients are available per trial per year. And some trials require large numbers; it takes years to accrue enough patients, and many trials never do.
3. Phase 3 trials are too long and inflexible. In the last 25 years, only one phase 3 glioblastoma study showed a statistically significant improvement in survival, adding only 3 months to median survival. As patients are treated, we learn how to use the treatments better, but the rigid structure of a phase 3 trial doesn’t allow for modifications midstream. Rather than stop a trial, discard the results and start over, researchers complete a trial anyway, knowing that there may be a better way to use the drug.

I propose an alternative approach:

1. All patients must be watched in a regulatory-grade registry so we learn from every patient—not just the 10% who may not even represent the typical patient.
2. A formal randomized trial is perfect to prove that a combination works, but we are not yet at the point where we have a combination worthy of a full-scale phase 3 trial. So, if a patient desires entry into a formal trial, I propose they be given access to the registry to pick the most promising trials.
3. We need a system in which experimental treatments get fast conditional approvals when they are shown to be relatively safe, with early evidence that they have the intended effect—even if that effect doesn’t result by itself in prolonged life. This allows us to use them in combinations and figure out how best to use them.
4. Paying for medical drugs is a problem. The only way this can work is if patients do not have to pay high costs for their treatments, and if drug companies get paid for the treatments. This will allow access to the drug. The Virtual Trial system should keep drug costs down, as it will take the vast majority of time and money out of the drug development process and break the monopolies currently preventing many new drugs from being developed. In fact, I have proposed a bill (see below) that basically requires Medicare and Medicaid to pay for them and encourages private insurance to pay. We are working out the exact wording and are considering a “pay for performance” model, or a compromise in which costs for non-standard treatments cannot exceed what the standard of care would have cost.
5. Doctors, or teams of researchers, can then think up the best combinations for each individual patient, and test them in small, fast, inexpensive (or free) virtual trials. They can see the ongoing results in all patients and quickly determine if a conditionally approved drug is worthy of continued usage—perhaps tweaking how it is given or the combinations used, or if it should be dropped. Once the ultimate cocktail is found, it can then be tested in a formal phase 3 trial.

I have been working on the components of this plan. We already have “right-to-try” laws passed in the U.S., but these did not work out as intended, mainly because of cost issues and fear that the FDA would hold usage of this pathway against a drug company. So, I am now working on a much-improved version of early access called the “Promising Pathway Act,” which was recently introduced into Congress. It fixed most of the problems with right-to-try laws and the FDA’s Accelerated Approval Program. It provides for conditional approval of treatments and requires all patients who use any conditionally approved drug to participate in a registry.

My organization, in partnership with Cancer Commons and its for-profit spinoff xCures, has set up a patient-navigation program that should be the model for how we approach all serious diseases. Our team of neuro-oncologists, PhD researchers, and nurse navigators—aided by an artificial intelligence engine—can look at our rapidly growing patient registry (we now have over 1,250 patients) and evaluate medical research, the rationales presented in tumor board meetings, and patients’ medical histories in order to come up with a list of treatment plan options that may be best for any given patient. The patient and their own doctor can select a treatment from our list, or they can elect to try whatever other treatments they want. Whatever they choose, our team then follows up on every patient to see the outcome of their chosen treatment. This way we learn from every patient.

We try to help patients get access to their chosen treatments, but the most promising options are usually impossible to access because the components are not yet approved, and either they are unavailable under expanded access or the drug companies won’t allow us to combine the experimental drugs.

Nonetheless, any doctor or researcher who is using a new combination of FDA-approved drugs for a patient can submit that treatment plan option to our system to be run as a virtual trial, allowing the doctor or researcher to quickly test the theory in their patient and use our system as a screening tool. They can try many combinations quickly, and if a particular combination shows a lot of promise, it can then be promoted to a traditional phase 3 trial to validate the findings.

Any treatment plan options validated in this way would be made up of FDA-approved treatments, so any doctor could prescribe them, allowing every brain tumor patient to have access—not just those perfect patients that fit into existing clinical trials.

In summary, our Virtual Trials could be used as a screening tool to figure out the best combinations, and how best to use treatments, which then can be tested in formal trials. Conversely, this approach could be used to quickly eliminate bad combinations. Having all results available in a central registry would help doctors from around the country avoid trying the same ineffective combinations.

Dr. Musella can be reached at musella@virtualtrials.org.