By Teri Heiland, Ph.D and Bill Watt, Ph.D.
Cancer immunotherapy marks a turning point in our fight against cancer. It’s been called the scientific advancement of the year by the American Society of Clinical Oncology. Essentially, this class of medicine unleashes the existing potential of the human immune response against cancer. What has the entire industry excited is that a fraction of patients on immunotherapy medicines have long outlived previous survival estimates; some have seen their tumors disappear.
However, the reality is that immunotherapies are only available for a few cancer types, and the majority of patients will not see a long-term response.
The prevailing thought is that immunotherapies depend on having a diverse population of immune cells infiltrating the tumor environment. This requirement is now believed to be met in perhaps one in five of cancers that involve solid tumors, which may explain why only a few people respond to these drugs.
To overcome this barrier, scientists at Immunomic Therapeutics and EpiThany are looking at cancer immunotherapy differently than current, prevailing approaches. Instead of developing medicines that rely on a latent immune capability that may or may not be present, we are designing cancer immunotherapies that have the potential to reprogram the immune system, mounting a comprehensive anti-tumor immune response.
The early results of Phase I clinical testing, using this approach in glioblastoma and cervical cancer research are spurring additional research and development.
GOOD COP, BAD COP
Our immune system is an alliance of specialized cells with complementary roles. When it encounters an enemy, it may unleash its fury on tumors with cytotoxic T-cells and inflammatory molecules in what is known as the Th1 response. A strong Th1 response is what is responsible for what we sometimes see with available cancer immunotherapies.
On the other hand, the immune system generates a Th2 response that repairs damaged tissue, is anti-inflammatory and is thought to functionally neutralize Th1 responses.
The balance in this immunological yin and yang is set by a specialized immune cell called the CD4+ T-cell. It determines whether a given immune response will be predominantly Th1 or Th2, and coordinates the responses of other immune cells. This choice is determined by antigens, bits of host and foreign cellular material.
Faced with cancer, the CD4+ T-cell may often err on the side of caution. Because tumors retain many qualities of the normal cells from which they arise, tumor-derived antigens presented to CD4+ T-cells can be misinterpreted as normal tissue, leading to a predominantly Th2 or mixed Th1/Th2 response.
But what if there were a way to target CD4+ T-cells so it could specifically provoke a Th1 response? Together, Immunomic Therapeutics and Epithany are both studying novel approaches to cancer immunotherapy, in hopes of directly reprogramming the CD4+ T-cell to create Th1 responses.
In this potential approach, scientists are utilizing circularized DNA molecules that are specifically designed to carry genetic blueprints for the anti-tumor response in a form that the CD4+ T-cell’s machinery can recognize. Circularized DNA is believed to be stable, safe, easy to manipulate, and can be injected into the patient’s skin.
Immunologists at EpiThany have developed a way to systematically analyze the molecular sequences of tumor antigens, identifying those that may potentially stimulate a potent Th1 response. Circularized DNA molecules encoding those antigens can then be created.
The final step in this approach would involve delivery: Immunologists at Immunomic Therapeutics, Inc., are working on a way to get information encoded by the DNA to CD4+ T-cells through the labyrinth of the immune system. ITI’s founders invented a way of attaching the DNA sequence encoding the Lysosomal Associated Membrane Protein (LAMP) to an antigen coding sequence that could serve as an express route to CD4+ T-cells.
Combining the LAMP DNA sequence with a specific Th1-provoking DNA sequence may ensure that the crucial instructions are delivered to this key immune cell and could form the foundation for a new type of cancer immunotherapy.
PHASE I & II STUDIES
Early Phase I studies of the investigational LAMP-based immunotherapy have been conducted in glioblastoma multiforme, an aggressive brain cancer, and in acute myeloid leukemia, a devastating cancer of the bone marrow and blood. Phase II trials of LAMP-based immunotherapy have begun for people with glioblastoma.
Separately, in an early Phase I study of EpiThany’s DNA-based Th1 vaccine for treatment-resistant ovarian cancer that met its primary safety endpoints, women were also monitored for survival, and the median survival for the subjects demonstrated improvement over matched historical controls. Subjects enrolled in this trial showed a steadily increasing Th1 immune response against the tumor antigen. It is believed that an increase in immune responses against specific tumor antigens may suggest that the immune system is beginning to recognize and overcome the tumor’s ability to hide from it.
These results are preliminary. However, reprogramming the immune system with genetic instructions could represent the next wave of cancer immunotherapy research. The combination of LAMP with specific Th1-invoking DNA sequences may also be stronger than each approach on its own. In the end, DNA-based immunotherapy may not be a panacea for cancer, but it could be an important catalyst to finding a cure.