Q&A: Strengthening hopes in cancer -- Immunology and combination therapies

A talk with Dr. Edward Bradley of MedImmune about his company’s role in the AstraZeneca family and the place MEDI4736 potentially holds within the overall pharmaceutical franchise

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Asked by DDNews to describe how MedImmune fits into the AstraZeneca family and to define its particular strengths, Dr. Edward Bradley, senior vice president of R&D and head of the Oncology iMED for MedImmune, says, “MedImmune is the global biologics research and development arm of AstraZeneca. We comprise approximately 50 percent of AstraZeneca’s overall pipeline, a testament to our strong scientific innovation. We are focused in three core key therapeutic areas: oncology; respiratory, inflammation and autoimmune disease; and cardiovascular and metabolic disease. We are also opportunistic in infectious disease and neuroscience.”
In addition, he notes that MedImmune has successfully discovered, developed and applied a number of innovative technologies, including antibody engineering, cell culture production and live viral vaccines. MedImmune recently developed a fully human monoclonal antibody molecule that carries its proprietary adaptation (YTE technology), which extends the molecule’s half-life.
DDNews: As announced in early June, MEDI4736 has progressed into its first Phase 3 study: “MEDI4736, an investigational, engineered, human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. It is believed that by targeting PD-L1, MEDI4736 may block this ligand from sending out signals to T cells to ‘ignore’ tumor cells, thereby countering cancer’s immune-evading tactics.” Please tell our readers more about this molecule’s mechanism of action and the promise it holds.
Edward Bradley: MEDI4736 is an immunotherapy molecule, meaning it is designed to empower the immune system to counteract the tactics used by cancer cells to avoid detection and attack the tumor. Tumors can avoid detection from the body’s immune system by expressing the programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Blockade of PD-L1 may help overcome these immunosuppressive effects and restore T cell activity against tumors. In preclinical experiments, inhibition of PD-L1 has been shown to produce durable antitumor activity as a single agent and in combination with other therapies.
We’re extremely pleased with the data we’re seeing with MEDI4736. In its Phase 1 dose escalation study, reduction of tumor burden was seen at multiple dose levels as early as six weeks, and the data demonstrated durable clinical activity and tolerability in patients across a range of solid tumors. The molecule has recently been accelerated to Phase 3 development for non-small cell lung cancer (NSCLC).
For the industry, this really is a transformational time. There is so much excitement surrounding immunotherapy and we believe that MEDI4736 has the potential to play a key role in this area. Data suggest that PD-1/PD-L1 modulation might become the basis of future cancer regimens, either as monotherapy or in combination with other active molecules.
DDNews: As the Phase 3 announcement discussed, MEDI4736 appears to be active against a broad range of cancer types. What are the theoretical underpinnings that support this somewhat unusual profile?
Bradley: In a Phase 1 dose-escalation study of MEDI4736 in 27 patients with advanced solid tumors, reduction of tumor burden was seen at multiple dose levels in as early as six weeks. The tumor types in the escalation phase were NSCLC, melanoma, colorectal cancer and renal cell cancer. In the expansion phase in approximately 350 patients, early evidence of clinical activity was reported in multiple tumor types: NSCLC, squamous cell carcinoma of the head and neck, pancreatic cancer, gastroesophageal cancer and cutaneous melanoma.
This efficacy across a range of tumor types is reflective of the unique attributes of the immune system: just as the immune system can detect a foreign substance, immunotherapies can detect small changes on a cell surface damaged by cancer. This recognition process occurs regardless of whether the tumor was resistant to previous therapies, so we’re seeing responses in first-line settings but also after multiple lines of chemotherapy and radiation.
DDNews: Like immunological therapies, combination therapies are frequently cited in the literature as holding renewed promise. How do the mechanisms of action differ between a PD-L1 therapeutic and, for example, tremelimumab, that makes this approach more effective in some cases than monotherapy?
Bradley: Cancer attacks the body by hijacking multiple immune checkpoints to escape detection. As a result, targeting more than one checkpoint with combination therapy produces a rapid and more durable response in a greater number of patients. MEDI4736 and tremelimumab target non-redundant pathways—PD-L1 and CTLA-4—to fight cancer, working at different checkpoints to engage the immune system to possibly overcome cancer’s immune-evading tactics. In one mouse study, combining agents that target PD-L1 and CTLA-4 produced synergistic effects and led to complete tumor regression.
Combination therapy has the potential to be one of the most effective ways of treating cancer. This approach is a strategic focus, and because of our access to the AstraZeneca and MedImmune combined portfolios, we are uniquely positioned to explore combinations and have already initiated multiple combination studies.
DDNews: AstraZeneca’s chief medical officer, Briggs Morrison, has been quoted as saying, “We believe that our rich oncology pipeline has the potential to redefine the way that cancer patients are treated (emphasis mine).” Please describe how and why this is true.
Bradley: AstraZeneca/MedImmune are tackling four key mechanisms in oncology— immuno-oncology, tumor drivers and resistance, DNA damage response and armed antibodies/antibody drug conjugates, and we have a rich portfolio to support these four areas.
I have been spending a lot of time in immuno-oncology, which represents a major turning point for the treatment of cancer. We are building a broad portfolio in this area to actively explore monotherapy and multiple combination therapies across a range of tumor types. We believe combination therapies may have the potential to be one of the most effective ways of treating cancer, and we are well positioned to pursue the most effective, data-driven immunotherapy combinations given the AstraZeneca and MedImmune combined portfolio.
DDNews: Also, can you expand on each of MedImmune’s other core areas of research?
Bradley: Oncology is certainly one of our key therapeutic areas, and we’re at the forefront of developing exciting new therapies. But we’re also very proud of the work we’re doing in other research areas, including for respiratory, inflammation and autoimmune diseases, such as asthma, idiopathic pulmonary fibrosis, systemic lupus erythematosus, rheumatoid arthritis, chronic obstructive pulmonary disease, multiple sclerosis and psoriasis. Our unique personalized healthcare approach in this area aims to improve the drug development and patient care processes, by helping us identify the right drug, the right target and the right patient as quickly in the process as possible.
Another key focus area of ours is the cardiovascular and metabolic disease space, where we’re developing novel drugs to treat obesity, diabetes and cardiovascular disease. MedImmune is also pursuing opportunity-driven growth in infection & vaccines and neuroscience.
Edward Bradley, M.D., joined MedImmune in August 2010, as vice president of clinical development, oncology. A board-certified medical oncologist, Dr. Bradley earned his medical degree and completed his medical residencies at Harvard University. He conducted his clinical oncology training in the Medicine Branch of the National Cancer Institute and was a fellow in Robert Gallo’s laboratory. He returned to the Harvard faculty as director of the Laboratory of Tumor Cell Biology in the Beth Israel-Brigham and Women’s Hospital and has maintained a career-long involvement in immunologically focused therapies for cancer.
As head of oncology for CETUS, he led the development and registration of interleukin-2 (ProLeukin) for renal cell carcinoma. He initiated and led Sterling Oncology and the Sterling-Winthrop Immunoconjugates Division, a subsidiary of Eastman-Kodak, and initiated the U.S. development of oxaliplatin (Eloxatin) following its acquisition by Sanofi. Prior to joining MedImmune, Bradley was vice president and head of oncology development at Incyte and conducted the registration trials for ruxolitinib (Jakafi).

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