|T cells (Blue) attacking a cancer cell (white) in vitro. From The Center for Cancer Research|
The popular media has all been a buzz this week over an exciting new study about a new possible cancer treatment. As a PhD Immunology Student, I have to begin by complementing NPR science reporter, Joe Palca for his post on the NPR Health Blog, Shots for 1) describing the basics behind immunotherapy in a way for the public to understand and 2) for "warning" the reader that the sample size is very small and that this is preliminary research. Both points are important to state clearly, as often we, the public, reads a brief story about a new therapy and we instantly want to use it and have it work 100%. Although, the sample size of this study was merely 3 individuals, the fundamental technique and findings offer great promise in the development of the most effective, least invasive treatments to combat cancer.
Gene Therapy: Engineering Cells to Cure Disease
|Basic procedure behind gene therapy whereby a patient's own T cells are isolated then engineered to express a certain protein it didn't express before, then the engineered T cells are injected back into the patient to help fight the disease. From attack-cancer.org|
One of the first human-based study that gene therapy was used to treat babies born with severe combined immunodeficiency (SCID). SCID is named as such because people born with this genetic disease, have essentially no immune system making them incredibly susceptible to illnesses-think David Vetter aka “The Bubble Boy”. One of the most common causes of SCID is a single genetic deficiency in a gene called adenosine deaminase (ADA). ADA is important in the building of new nucleotides for DNA synthesis, and as you might imagine, without this ADA enzyme, DNA synthesis ceases and without the ability to generate new strands of DNA, cells die when they divide. So ADA-deficiency largely affects highly proliferating cells, like your B and T cells. To treat ADA-deficiency, stem cells are isolated from the patient and sent to a laboratory, where the cells will be transduced with a viral vector. This virus is not immunogenic and is just used as a vector-something to deliver the ADA gene to the cell. Once the virus gets in, it will insert the ADA gene into the DNA of the isolated patient’s cell. The power of genetic therapy is great since what happens is “fixing” cells to express a necessary gene, like ADA, that the cells didn’t express before! Once the cells express ADA, they are transplanted back into the patient, where theoretically the person is cured of their genetic deficiency.
However, there are many challenges to genetic therapy, which scientists have struggled with including: how to make the newly injected “fixed” cells last longer? These cells don’t seem to survive very long in the patient post transplantation, requiring patients to undergo this treatment over and over. Another concern is the lack of control of where the gene of interest inserts. For example, sometimes the gene is inserted in an unstable location, and cells lose the expression of the inserted gene over time.
Since the early 1990’s when gene therapy was used to treat ADA-deficiency, researchers have used this genetic technique as a means to treat a variety of human diseases including Parkinson’s Disease, myeloid lymphoma, and HIV. With each trial, comes better understanding and innovations in perfecting the therapy to enhance its effectiveness.
The Molecular Immunolog:Re-engineering Our Immune System to Kill Cancer
|Creating Chimeric Antigen Receptors (CARs) by piecing together signaling components from different proteins using molecular biology. CART19 would look similar with the anti-tumor extracellular domain to recognize CD19 with the intracellular TCR signaling domain. From DiscoveryMagazine.com|
If you apply this same concept to eradicating a cancerous tumor, by having T cells that could recognize tumor cells and kill them, you could develop a therapy that would lessen the requirement of using painful chemicals and drugs to solely fight cancer and circumvent rejection issues since the treatment is using the patient’s own cells to kill the tumor (versus bone marrow transplant from another person, where graft-verse-host disease is a possible danger).
So how did June and his research team do this? They engineered a gene-construct in the lab consisting of an extracellular domain that recognizes a protein only expressed by B cells (CD19) fused to an intracellular signaling component of the T cell receptor (TCR). With this strategy, T cells would be able to recognize B cells, become activated, proliferate, and subsequently kill their targeted B cell. This sort of genetic engineering is a forte of June’s laboratory and is called chimeric antigen receptor (CAR) generation. The clinical trial was appropriately titled "CART19" (CAR+ T cells for CD19).
By transducing the CLL patients’ isolated T cells with a viral vector containing this CAR, then injecting these CAR+ cells into the CLL patients, they found that the “engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months …moreover, a portion of these cells persisted as memory CAR+ T cells…” The authors of the study explain that these memory B-cell reactive T cells “may provide a mechanism for CAR memory by means of “self-vaccination/boosting” and, therefore, long-term tumor immunosurveillance”! This exciting research really puts forth the idea that we are on the right track to discovering the ultimate treatment for cancer patients- a treatment that consists of as little pain, money and tumor re-occurrence as possible. Utilizing the body’s own defense system to fight cancer, with the potential ability to fight the tumor over and over again without further injections and drugs, may represent an ideal cancer therapy!
The patients who participated in this study all had “advanced, chemotherapy-resistant CLL”. Two of three patients in the study are in remission 10 months post CART19 infusion; the third still has the disease. The researchers acknowledge that chemotherapy still plays in a role in fighting tumors, and that chemo is likely to have played a role in the success of their CART19 therapy. It is important to consider, that this research-however exciting-is still in the very early stages of development and much is left unknown including: 1) how long these CAR+ memory T cells live for and if their effector function is still in tact, 2) how healthy B cells are affected by this therapy, since the targeted protein, CD19, is expressed by all B cells-tumor and healthy ones and 3) if there are any long-term side effects of using the particular virus vector used in this study. Importantly, all three CART19 patients are still being monitored to further address these questions.
Porter DL, Levine BL, Kalos M, Bagg A, & June CH (2011). Chimeric antigen receptor modified T cells in chronic lymphoid leukemia. The New England journal of medicine, 365 (8), 725-33 PMID: 21830940