Immunotherapy: The next generation of treatments

Investigator: Svetomir Markovic, M.D., Ph.D.

"The idea is to figure out how we can attack cancer with as many targets as possible without putting the patient through invasive and potentially harmful procedures."
Svetomir Markovic, M.D., Ph.D.

Dr. Markovic and his research colleagues are investigating a solid tumor - malignant melanoma, for which there is no effective treatment and non-Hodgkin lymphoma (NHL) for which there is treatment but the tumor often comes back after treatment, and when it does, it is rarely treatable. In his research to develop new immunotherapies, Dr. Markovic is investigating these two different forms of cancer as disease models. They are using these both adaptive immune system strategies and non-adaptive immune system strategies -- two extremes -- to test immunologic interventions because both have evidence of positive outcomes.

Adaptive Immune System Strategies: Aerosol Cancer Vaccines

This strategy improves vaccine technology by delivering them in combination with other molecules, or delivering them through unusual routes such as inhaling an aerosol vaccine instead of injecting it under the skin, or into a muscle. An aerosol delivery system is appealing because his laboratory observations show high concentrations of T cells in the blood vessels of the lung, which means they're easily accessible by an inhaled spray. Devising an aerosol-delivered antigen could quickly and effectively reach the T cells that launch an immune response. The researchers use a molecule called granulocyte macrophage colony stimulating factor, GM-CSF for short, administered to the lungs as an aerosol spray in addition to the aerosolized cancer vaccine. Once in the lungs, this molecule helps drive the immune system to recognize the cancer as foreign and attack the tumor. After the attack is begun, the body develops its own vaccine against the tumor while the tumor is still in the body.

The experimental GM-CSF Aerosol Vaccine is now in the second phase of development in which researchers are trying to identify the most effective dose for humans. Other related ideas are being explored on the adaptive side of the immune system to refine the concept of creating vaccines within one's own body.

Non-Adaptive Immune System Strategies: Harnessing Natural Killer Cells

Cancer cells become lethal when they reproduce themselves so much that they overtake a healthy body. They have many attributes and abilities that enable this robust growth. Cancer cells can become completely invisible to the T cell arm (the adaptive side) of the immune system by changing one molecule on the surface of the cell. When the cancer cells lose this molecule - and it's the most common escape mechanism from T cell immunity that cancer cells have - the T cell system becomes ineffective. Once this change to "invisible status" is made by cancer cells to evade the T-cells, a key line of the body's defense is lost. However, the loss of the molecule that leads to T cell evasion by the cancer cell also targets the cancer cell for attack by the other arm of the immune system: the non-adaptive arm. This includes natural killer cells. Dr. Markovic's group is investigating new uses for an old discovery--a molecule discovered in the 1950s called Interferon. Once widely hailed as a promising cancer "break through" decades ago, interferon's early studies as a chemotherapy agent didn't live up to expectations. As a result, it was all but abandoned as a cancer drug. Now Markovic's research team is using Interferon in a different capacity: as a hormone, a regulator of the immune system.

Non-Hodgkin Lymphoma Studies

Non-Hodgkin lymphoma spreads throughout the circulating lymph fluids of the body. Yet, like malignant melanoma, is an extreme kind of cancer. While effective treatments exist for this cancer, there are serious drawbacks. In those patients who suffer a recurrence, the cure rate from this second occurrence is quite low. Treatment also involves blood and marrow transplants in efforts to be able to give high doses of chemotherapy. Dr. Markovic and his colleagues are exploring a new therapy involving natural killer cells that they also study in their melanoma solid tumor work. Patients who develop a particular complication from allogeneic transplantation (the type that involves transplantation of donor, rather than the patient's own stem cells) have a lower risk of cancer recurrence than those who do not get the complication. Patients who undergo allogeneic transplantation are at risk for graft-versus-host disease (GVHD, which is when the transplanted (graft) cells recognize the patient (host) cells as foreign and attack them. As a result of developing GVHD, the introduced donor's natural killer cells are activated to kill those cancer cells that survive the chemoradiotherapy.

The researchers are developing a variant of a transplant that would is maximize cancer treatment while minimizing toxicity. This novel immunotherapy eliminates the risk of GVHD while also retaining the benefits of stem cells' regenerative powers. In addition, as a result of their work in melanoma surgery Markovic's group also observed that timing is critical. They realized that the ideal time to administer immunotherapy is one week prior to surgery. The team's most recent results from animal model studies suggest that if the dose of natural killer cells in a transplant graft is sufficient, it will lead to a cure for non-Hodgkin lymphoma in mice.