Before the NMTRC moved it’s headquarters to Grand Rapids Michigan it started out in Burlington Vermont. While Dr. Sholler had her lab based in UVM she started many long lasting collaborations with clinicians and researchers across the country. However one of these lasting collaborations took place in Vermont and is very unique. Why? Because this extraordinary surgeon and researcher has spent his entire career focused on Breast Cancer.
He and Dr. Sholler were kindred spirits in their approach to research and soon enough. Dr. Krag began doing some work with neuroblastoma. He is a brilliant and passionate researcher whose work we started to help fund in dribs and drabs – this work still blows my mind – and thanks to your support we were able to send another $20,000 to help continue this pre-clinical work. I look forward to sending the proceeds from one of our events in the future to fund this as a clinical trial.
This is what we mean when we say that we “Celebrate with a purpose!” You came out to Cure Me I’m Irish in March and soon after $100,000 went to fund the Phase II DFMO study and $20,000 went to Dr. Krag who I asked to explain to you below just what we are funding.
It is remarkable.
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The Problem
Extensive research has clearly demonstrated that the relationship of a cancer to a person’s immune system results in priming of the immune system. Priming means that the immune system begins to react to the tumor and initiates a tumor-specific response. This activity begins very much like the response to an infection in which the immune system reacts quickly to the infecting organism. The problem with cancer is that the next step, amplification or boosting of that immune response, does not occur.
There are many reasons for the lack of a boost, but overall, the cancer is responsible for blunting and ultimately evading the immune response. This results in profound immune suppression specifically related to the tumor. Hundreds of clinical trials have focused on methods to overcome this tumor-induced suppression.
However, evasive methods used by the tumor are extremely complex and overlapping. When one aspect of suppression is overcome, there are multiple additional suppressive mechanisms that emerge to again blunt the immune response. Our approach will be to side step the entire suppressive capacity of the cancer by boosting the immune response in the lab. We can successfully amplify the immune response outside the patient away from the suppression of the cancer. Once we have amplified the immune response we can return the amplified immune materials safely back to the patient.
How can this be achieved?
The priming step in the immune response occurs in lymph nodes that receive drainage from the cancer. The lymph node is a mini-immune organ filled with special cells that respond to foreign challenges. Two major types of immune cells in the lymph nodes are T cells and B cells. These cells have special molecules on their surface that act like handles to grab foreign things. During the priming response, the T and B cells undergo remarkable changes. In response to a challenge, they first rapidly grow and divide. Then each time they divide into daughter cells, they change their handle so that it can better grip the foreign stuff. In a matter of days, not only are there millions of daughter T and B cells, but their handles can now grip the foreign material with exquisite accuracy. Gripping the cancer prevents it from growing. This is nature’s phenomenal method to defend against foreign non-self things.
After the priming response the lymph node is filled with T and B cells that have been educated to grab and deactivate foreign stuff and this includes cancers. The next step, the boosting step, should lead to greatly increased growth of these educated T and B cells. However, these cells, ready to go out into the world and do their duty are turned off by the cancer. This is where we come in.
I developed a radiotracer method of identifying the exact lymph node receiving drainage from a cancer. That same method can be used to precisely identify a lymph node draining a cancer. We will use this method to help boost the immune response to a neuroblastoma. First we will obtain neuroblastoma cells from a patient and make a vaccine from their own cancer. It will be treated so that it cannot grow. Then the tumor vaccine will be injected into the skin of the thigh. The tumor parts in the vaccine will drain to a lymph node in the groin area. The lymph node receiving this non-living tumor material will respond. It will undergo a priming response specifically to the tumor vaccine. The T and B cells will respond by growing and by altering their handles to specifically bind and grab the tumor. This priming step takes only a few weeks.
After priming with the vaccine, the radiotracer method will be used to find the vaccine-draining lymph node and it will be removed using a small surgical procedure. Then the lymph node will be processed in the lab so that all of the T and B cells will be boosted. This will be done by growing them using special methods.
The B cells are the cells that make antibodies. We have shown that each lymph node contains many, many different B cells that make antibodies that target the cancer. Once we have grown the B cells we will generate and purify large amounts of the the anti-cancer antibodies. These antibodies, now boosted to high levels, will be administered intravenously back to the same patient they came from. This completes the circle. We have simply provided the boost in the lab to the cells primed by the body.
The value and the challenges of this approach:
It is now clear that cancers are very different just as people are very different. Careful analysis of the genetic code of neuroblastomas show them to be different in hundreds of ways. Even within one cancer the cancer cells are different.
Our focus is to take advantage of the ability of the immune system to generate a response to very complex targets. The immune system is good at thisl. By using the patients own cancer as a vaccine, the initial priming response occurs in the vaccine-draining lymph node. We then boost the response in the lab. What is returned to the patient are many different antibodies and T cells that are educated to deal with the complex neuroblastoma. Each patient generates their own treatment to their own tumor.
Also, it is well known that cancers develop resistance to an anti-cancer drug. After the tumor regrows it is resistant to that drug. This is a big problem. We expect that even with our complex immune treatment that cancers will figure out how to become resistant to the antibodies and T cells that we give back to the patient.
But, when the tumor recurs and is resistant it will somehow be different. When that happens we will make a new vaccine from the newly grown resistant tumor and let another lymph node prime the T and B cells to this new form of resistant cancer. We simply repeat the whole process as if it were a new tumor and again give the boosted T cells and antibodies back to the patient.
This may be one of the only treatment plans that really is a process not a single fixed drug. In this approach, the inevitable onset of resistance may finally be taken care of.
Where are we now and where do we go from here?
We have come a long way in obtaining important preliminary data. With your help we hope to soon begin the first steps and vaccinate cancer patients. I invite and gratefully welcome your support to make this critical step happen. We all work together. This problem is completely solvable.
David Krag, M.D.
December 12, 2012
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