Shooting for the Moon in Honor of Mesothelioma Awareness Day

As Mesothelioma Awareness Day approaches, it's the perfect time to raise awareness about this rare form of cancer and the amazing potential for progress now in sight thanks to the Cancer Moonshot project. Established in 2004, Mesothelioma Awareness Day (September 26th) exists to bring funding and attention to mesothelioma, a rare yet aggressive and deadly form of cancer. So, how much can the Cancer Moonshot do to bring an end to Mesothelioma?

Mesothelioma

Mesothelioma is a rare form of cancer, with only about 2,000 to 3,000 new cases annually in the US. In cases of malignant mesothelioma, cancer cells form in the thin layer of tissue lining the abdomen, chest wall, or lungs, or, less commonly, in the testicles or heart. Long-term asbestos exposure is the primary cause of malignant mesothelioma in adults. This exposure puts not just the person who was originally exposed at risk, but also that person's family members. This kind of malignant mesothelioma typically takes 10 to 40 years to develop after exposure.

Pediatric mesothelioma is different in that it can spontaneously generate and does not necessarily have a link to asbestos exposure. In fact, most cases of pediatric mesothelioma seem to have no apparent cause, making prevention difficult. It is also exceedingly rare, as most cases of mesothelioma are in older adults.

The Cancer Moonshot and Data Siloing

In January of 2016, President Barack Obama announced the Cancer Moonshot project during his State of the Union address. The goal of the initiative is to double the amount of research progress in the fight against cancer by putting more money, cooperation, and focus on the most promising areas; by making more therapies available to more people; and by ensuring that the siloing of cancer research data comes to an end. The initiative is led by Vice President Joe Biden who directs the Cancer Moonshot Task Force; they are advised by the National Cancer Advisory Board (NCAB) and its working group, the Blue Ribbon Panel dedicated specifically to the Cancer Moonshot.

The issues that the Cancer Moonshot have identified are perhaps not surprising to anyone who is passionate about rare diseases generally or a specific rare disease such as mesothelioma. Nevertheless, they are notable and deserve our close attention.

First, the issue of siloing of data, research results, and scientific knowledge generally is a tremendous problem for all sufferers of rare diseases—people who make up about ten percent of the US population. While cancer immunotherapy, combination therapies, and genomics hold incredible promise for patients, siloing means a lack of access and progress.

As of the time the Cancer Moonshot was announced, only about 5 percent of American cancer patients participated in clinical trials for new treatments. Most of them don't have access to their own results and data. Furthermore, most oncologists simply don't have access to the latest advances in treatment research and technology.

Historically, the raw scientific data collected by researchers throughout the course of studies becomes the property of the institutions that the researchers work for. The end result is mountains of data locked away in each individual research institution, but no central repository from which truly groundbreaking conclusions and progress may spring. The need to detect biological and genetic patterns that could reveal the mechanisms that enable cancer to manifest and grow makes sharing and collaboration essential.

The Cancer Moonshot initiative has now identified one of its key goals: the creation of a National Cancer Data Ecosystem. This would be a free “one-stop shop” for research data on cancer available to patients and researchers alike. Patients could upload their own data and in turn receive information about their particular variety of cancer.

Collaboration is also going to be critical for making new treatments like immunotherapy more effective. Currently, only 20 percent of patients get the full benefit of immunotherapy treatments. Researchers hope that by pooling all existing knowledge about immunotherapy treatments and practices more effective forms of immunotherapy might be developed.

This kind of information sharing should also benefit genomics treatment projects such as the Collaborative Cancer Cloud. This project aims to create tailored gene therapies for each patient, and to do that it needs to access huge amounts of data on genetic mutations, cancer surveillance, and treatment effectiveness.

New Treatments Arising from Moonshot Research

In September 2016, the Blue Ribbon Panel reported back to the Vice President with recommendations for the rest of the Cancer Moonshot initiative. The report contains ten suggestions which will form the “research blueprint” for the rest of the project.

Cancer Immunotherapy in Focus

Ideally, the body's natural immune system works to prevent cancer by detecting and destroying cells that are abnormal. However, cancer cells can sometimes avoid being detected and destroyed by the body's immune system. They have several ways of avoiding the defenses of the human immune system:

• Some cancer cells make it harder for the immune system to see them by reducing the expression of tumor antigens on their surface;
• Some cancer cells inactivate immune cells by expressing proteins on their surface; and
• Some cancer cells can both promote their own proliferation and survival and suppress immune response by inducing surrounding cells to release immune suppressing substances.

Knowing these tactics employed by cancer cells, researchers have pursued the field of cancer immunology, which has emerged over the past few years. The new techniques for treating cancer created in this field, called immunotherapies, all have the common goal of increasing the strength of immune responses to tumors. Immunotherapies can do this in several ways, but most methods boil down to countering specific cancer cells that suppress immune responses, providing man-made immune components, or stimulating smarter or stronger immune system responses generally.

So far immunotherapy is more effective against some kinds of cancer than others; for those varieties, immunotherapy alone may be enough treatment. For cancers that are less responsive to immunotherapy, at least so far, immunotherapy can still boost the effectiveness of other treatments when used in combination with them.

Several broader research questions related to cancer immunotherapy remain, and these too will be pursued as part of the Cancer Moonshot initiative:

• Why is immunotherapy effective in certain patients with one type of cancer but not in others who have the same type of cancer?
• How can we expand the use of immunotherapy to more varieties of cancer?
• How can we increase the effectiveness of immunotherapy by combining it with other treatments like chemotherapy, targeted therapy, and radiation therapy?

Kinds of Cancer Immunotherapy

Once you understand the many kinds of cancer immunotherapies already under development, it is easy to see why the Cancer Moonshot experts find this area so promising. Here are the kinds of cancer immunotherapy that exist today.

Adoptive Cell Transfer

In adoptive cell transfer, an experimental form of immunotherapy, some patients with very advanced cancers have been completed cured. These patients primarily suffered from blood cancers. ACT works when T cells from inside the tumor of a patient, called tumor-infiltrating lymphocytes (TILs), are collected. Those TILs are then tested to see which show the greatest recognition of the patient's tumor cells. Those selected are then grown into large populations in the laboratory and activated by cytokines, immune system signaling proteins. Finally, the treated TILs are infused into the bloodstream of the patient.

This works because the most successful T cells are multiplied and put back to work. With greatly increased numbers they can then shrink or even kill off the tumors.

A similar method is called CAR T-cell therapy. This works by collecting T cells from the blood and then genetically modifying them to express CAR, a chimeric antigen T cell receptor protein. Then, as in the other ACT technique the modified cells are grown into large populations and reintroduced into the patient. Once inside the patient, these new CAR T cells attach to the surface of the cancer cells and attack them.

Monoclonal Antibodies to Treat Cancer

The immune system can attack invading substances like cancer cells by manufacturing many antibodies, proteins that sticks to antigens, specific proteins carried by enemy cells. Once so “marked” by the antibodies the entire immune system can get involved and fight the cells that contain that antigen.

Monoclonal antibodies (mAbs) are antibodies designed to target a particular antigen like those found on cancer cells. Scientists can make these mAbs in large numbers in labs, and these can be used to treat some cancers. In fact, more than one dozen mAbs have been approved to treat various cancers by the US Food and Drug Administration (FDA).

Naked monoclonal antibodies are the most common kind of mAbs used to treat cancers. These work without any radioactive material or drug attached to them.

Conjugated monoclonal antibodies, also called labeled, loaded, or tagged antibodies, are joined to either a radioactive particle or a chemotherapy drug so that the mAbs can be used to locate cancer cells and take the treatments directly to them. This helps lessen the damage caused by these treatments to healthy cells.

Radiolabeled antibodies are joined to small radioactive particles. These are used in radioimmunotherapy (RIT). Chemolabeled antibodies, also called antibody-drug conjugates (ADCs), are mAbs that carry drugs, usually chemotherapy drugs. Both of these are types of conjugated monoclonal antibodies.

Bispecific monoclonal antibodies are drugs that contain two different mAbs; this allows them to attach to two different proteins simultaneously.

Some therapeutic antibodies bind to cancer cells and cause apoptosis or cell death. In other cases, the binding antibody is recognized by specific immune cells or proteins, which then cause the cancer cells to die by cytotoxicity.

Immune Checkpoint Modulators

Obviously, to work properly the immune system must be able to distinguish between normal, healthy cells and “invader” cells. It needs “checkpoints” to do this. Checkpoints are molecules on some immune cells that must be activated or inactivated in order to prompt an immune response. Cancer cells can sometimes avoid or use these checkpoints to avoid detection or attack; this is why treatments that target checkpoints are promising.

There are two kinds of cytokines, proteins that normally modulate or regulate the activity of the immune system, that are being used to enhance the human immune response to cancer: interferons and interleukins. Some of these proteins activate white blood cells like dendritic cells and natural killer cells.

Researchers are also working to develop more drugs that target checkpoint proteins on T cells such as PD-1 or PD-L1. These checkpoint proteins act as “off switches” for the immune system and are intended to protect healthy cells. However, these are also found on some cancer cells, a defense mechanism against attack.

Benefits of Immunotherapy

Cancer immunotherapy offers some clear benefits. First of all, it has the potential to fight many different types of cancer. Because it enables an effective response from the human immune system, effective immunotherapy would provide a universal cure for cancer. Immunotherapy is already effective against many varieties of cancer, including some that have resisted traditional treatments like chemotherapy and radiation (melanoma, for example).

Effective cancer immunotherapy is more likely to produce long-term cancer remission because it “trains” the immune system to fight and remember cancer cells. Longer lasting remissions could well be the result of the human “immunomemory.” Furthermore, many clinical studies on cancer immunotherapy have already demonstrated long-lasting beneficial results.

Cancer immunotherapy is less likely to produce as many terrible side effects as chemotherapy and radiation do. This is because it is more targeted and protective of healthy cells. Typical immunotherapy side effects resemble the symptoms of fighting off infection, such as fever, inflammation, and fatigue, although some immunotherapy carries with it more severe side effects mimicking symptoms of autoimmune disorders.

In all, the potential benefits of successful cancer immunotherapy are tremendous.

Conclusion

On the eve of the 12th Mesothelioma Awareness Day, the Cancer Moonshot has provided a new sense of hope and progress. With its focus on cancer immunotherapy and enhanced cooperation and access to information, the Cancer Moonshot reveals an intelligent approach that has an ambitious yet realistic goal. Mesothelioma awareness advocates hail the Cancer Moonshot as a commitment even to rare forms of cancer that are often overlooked, because the benefits are clearly going to be felt by our community.

From a rare disease perspective, the Cancer Moonshot model is particularly appealing. Will a success in this area provide a new paradigm for a more collaborative fight against rare diseases in the future?

Karla Lant is a freelance writer and editor who volunteers for the Rare Genomics Institute.