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New Cancer Immunotherapy Approach Seeks to Supercharge T cell Activity

Jun 11, 2018 10:06:00 AM / by Nancy Andon, MSc

HC Blood PackAn independent study [1] published by MedImmune/AstraZeneca cites the use of HemaCare leukopaks to assist in the development of a novel approach to treating cancer.

The new technique is based on an engineered protein named MEDI6383, and preliminary studies of its efficacy against cancer have been promising enough to launch a Phase 1 clinical trial.

The biggest hurdle doctors face when treating cancer is the inability of the body to distinguish between normal cells and cancer cells. Cancer cells are essentially normal cells that are damaged by mutations in particular genes. These mutations can result, first and foremost, in abnormalities in cell cycle regulation, causing cells to divide and grow uncontrollably. Mutations can also interfere with the immune system, making it difficult for immune cells to recognize cancer cells they way they would a foreign invader such as a bacteria or virus. It thus becomes very difficult to rid the body of cancer cells without damaging normal cells, which is why traditional treatments like chemotherapy and radiation are so hard on the patient. To get around this conundrum, cancer researchers have had to devise a new set of tactics.  The result is the promising field of cancer immunotherapy, a medical discipline designed to circumvent cancer cell-induced immune suppression by provoking an enhanced anti-tumor response.

The MEDI6383 study is a collaborative effort led by MedImmune and its parent company, AstraZeneca. The study is based on current research into using the body’s own immune system to fight cancer. In this particular case, scientists are using a fusion protein; one made up partly from an antibody commonly found in the human bloodstream, and partly from a human protein called OX40L. OX40L is a natural part of our body’s defense system; it binds to a T cell surface protein known as OX40. Activation of OX40 signals the cell to mount an immune response in a number of different ways, including cytokine production, proliferation, and resistance to T cell-mediated immune suppression. The antibody region of the protein not only allows the protein to interact with antibody receptors on immune cells, it can also improve the solubility and stability of its partnered molecule and increase the amount of time it will stay in circulation, thereby prolonging therapeutic activity.

Recent FDA approvals for monoclonal antibodies that elicit an anti-tumor response [2] show just how effective these molecules are. The strategy behind this type of cancer immunotherapy is fairly straightforward; they target molecules that regulate T cell activity. The best known of these therapies are probably the “checkpoint inhibitors”. [3] These antibodies target crucial checkpoints that inhibit T cells from full activation during normal physiological conditions. Where tumor cells encourage this response in order to effectively “hide” from the immune system, checkpoint inhibitors block immune cell suppression, permitting cancer cells to be targeted. 

Unfortunately, a significant number of cancer patients simply don’t respond to checkpoint inhibitors or may experience dangerous side effects such as inflammation, which can harm normal tissue. Clearly an alternative or complementary therapy was needed that can activate tumor-specific T cells by way of a different pathway.  The OX40 ligand (OX40L) provides such a pathway.

OX40L belongs to a superfamily of T cell receptors. It has diverse functions, including inducing apoptotic cell death in target cells, and acting as an immune cell stimulator to promote T cell activation and expansion. The authors hypothesized that their MEDI6383 fusion protein would also be able to protect T cells from immune suppression, since this ability had been reported for other members of the OX40 family.

In order to test their hypothesis, Dr. Shino Hanabuchi obtained fresh leukopaks from HemaCare, to isolate healthy human effector and suppressor T cells to carry out their experiments. Starting material sourcing, particularly for pre-clinical testing, is always an important consideration because precursor material quality impacts T cell functionality. [4, 5] Following purification, the MEDI6383 fusion protein was tested for its ability to bind native OX40 expressed on the surface of activated human and non-human primate (rhesus macaque) T cells. The scientists were pleased to show that their fusion protein did, in fact, potently bind OX40, and also enhanced T cell activation, signaling, and proliferation.

The next steps in the MEDI6383 study were even more important in determining the molecule’s potential value as a cancer therapeutic. Tumor cells are known to suppress T cell activity. Could MEDI6383 overcome this hurdle, and still enhance T cell function in the presence of tumor cells?

The authors used a specialized mouse model to address this question. Administration of MEDI6383 to the mice caused significant inhibition of tumor growth when compared with control mice. While these results were very encouraging, the scientists knew that mouse models don’t always reflect human physiological responses. To get a more accurate assessment of how MEDI6383 would affect a human patient, the authors decided to test the fusion protein in rhesus monkeys. MEDI6383 was administered to five rhesus monkeys over a course of three treatments.  The treatment induced the proliferation of both T cells and B cells.

All of these results taken together strongly suggest that MEDI6383 is a good candidate for clinical testing for anti-tumor activity in humans. The fusion protein is now being evaluated in a multi-center Phase-1 clinical trial in human cancer patients with solid tumors. It will be tested both as a stand-alone therapy, and in combination with an already established “checkpoint inhibitor” therapy.

The OX40 receptor is a promising new target in the world of cancer immunotherapy. Solving the problem of cancer-mediated immune suppression is one of the “holy grails” of cancer research, so this study and others like it are a very exciting step forward. Several pharmaceutical companies are now developing OX40 agonists as part of their research pipeline, and it will be very interesting to see how these and other T cell-based therapies develop.

References:

  1. Oberst MD, et al. Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein. Molecular Cancer Therapeutics. 17(5); 1024–38. May 2018.
  2. Callahan MK, et al. Targeting T cell co-receptors for cancer therapy. Immunity; 44:1069–78. 2016.
  3. Topalian SL et al. Survival, Durable Tumor Remission, and Long-Term Safety in Patients with Advanced Melanoma Receiving Nivolumab. Journal of Clinical Oncology. 32 (10); 1020-1030. April 2014.
  4. Bankhead C. New Clues to CAR T Cell Failure. MedPage Today. March 2018.
  5. Singh N, et al. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Science Translational Medicine. 8 (320); 320ra3. Jan 2016.

Topics: cancer immunotherapy

Nancy Andon, MSc

Written by Nancy Andon, MSc

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