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Science Corner: Our Growing CD Collection

May 06, 2013 | Alexandra Mulvey

The CD (aka cluster of differentiation) system is a way of classifying unique markers on cells that designate certain cell types, development stages, and functions. For example, CD4 is a marker for a class of T cells called “helper” T cells (a class that also includes, paradoxically, immune-suppressing regulatory T cells). CD8 is a marker for “killer” T cells. CD19 and CD20 are markers for B cells, while CD133 and CD34 may help in identifying populations of stem cells.

More than playing a role as markers, however, certain CD molecules have proven valuable targets for immune-based treatments. The CD20 B cell marker was the target for the first monoclonal antibody ever approved for cancer treatment, rituximab (Rituxan®). Since its approval by the FDA in 1997, rituximab has become the standard of care for patients with B cell lymphomas. Alemtuzumab (Campath®), which targets CD52 found on B and T cells, was approved to treat B cell chronic lymphocytic leukemia in 2001.

Today, targeting these markers has taken a distinct and highly promising turn. Instead of targeting them as markers of particular cell types that may be cancerous (as in the case of anti-CD20 therapies for B cell malignancies), a new kind of anti-CD treatment (sometimes called checkpoint blockade) has emerged that targets these molecules based on their role in stimulating or suppressing immune cell activity. An antibody targeting CD152, more commonly known as CTLA-4, recently became the first treatment ever proven to extend the lives of patients with advanced melanoma, the most deadly form of skin cancer. This treatment, ipilimumab (aka Yervoy™), was approved by the FDA in 2011. Another anti-CTLA-4 treatment, tremelimumab, is also in clinical testing and, because of an innovative deal with its developer, MedImmune, is part of the growing repertoire of promising experimental immunotherapies available for testing in our global cancer immunotherapy clinical trials network, the CRI/Ludwig Cancer Vaccine Collaborative.

Many more anti-CD agents that aim to exploit these pathways to improve survival outcomes for cancer patients are quick on the heels of these first-in-class therapies, however. Below is a rundown of some of the treatments targeting these pathways that are in clinical and preclinical testing.

CD279, more commonly known as PD-1, is a target for several drugs in development for many different cancers. Most advanced along the pathway is nivolumab (BMS-936558), which is being developed by Bristol-Myers Squibb (BMS), which also developed ipilimumab. BMS recently launched several phase III trials of the agent in kidney cancer, lung cancer, and melanoma. Nivolumab is also being tested in trials in combination with ipilimumab in patients with melanoma. Patient Mary Elizabeth Williams enrolled in one of these trials, directed by CRI scientist Jedd D. Wolchok, and experienced a dramatic remission and remains cancer-free today. You can see her story on our website here.  Visit our lung cancer and melanoma pages for more details on these trials (our kidney cancer page is coming shortly).

PD-1's partner in crime is CD274 (more often called PD-L1 or B7-H1), and drugs targeting this molecule are also showing promise in treating a number of different cancer types. At the 2013 meeting of the American Association of Cancer Research (AACR) and at our recent CIC Colloquium, scientists from Genentech reported encouraging results from a phase I trial of their antibody targeting PD-L1, MPDL3280A. Stay tuned for more results from this trial at the upcoming meeting of the American Society of Clinical Oncology, the largest cancer meeting of the year, which will take place May 30-June 4, 2013. An anti-PD-L1 antibody being developed by MedImmune, MEDI4736, is also among those agents being made available to our global trials network thanks to our innovative Clinical Accelerator model.

At our Colloquium, researchers also presented on a new antibody directed against CD137 (aka 4-1BB). Scientists Holbrook Kohrt and Ronald Levy showed that this drug (BMS-663513, aka urelumab) could significantly enhance treatment with traditional monoclonal antibodies such as trastuzumab (Herceptin®) and rituximab, the latter of which Dr. Levy developed in the 1990s. CRI funded the first studies to develop an antibody against 4-1BB in 1999 by Lieping Chen (then at the Mayo Clinic and now at Yale).

There are many more CDs to hail as targets for the next generation of immunotherapy: CD134 (GITR), CD134 (OX40), CD223 (LAG-3), CD278 (ICOS), and my two new favorite CD targets: CD47 and CD73. All of these are showing great promise to add to our ever-growing immunological arsenal against cancer. You can read more about the research on CD47 that CRI is funding on our breast cancer or ovarian cancer pages. For more information on CD73, read this 2010 review by former CRI postdoctoral fellow Bin Zhang, or this shorter 2012 review by John Stagg, a former postdoc with CRI scientist Mark Smyth in Australia.

In another avenue of anti-CD strategies, innovative immunotherapies are also targeting “classic” surface marker CD antigens in new and highly sophisticated ways, particularly the B cell marker CD19. New antibodies called bispecific T cell engagers (BiTEs) are designed to target CD19 along with CD3—a molecule expressed on all T cells—to bring them into contact to facilitate cancer killing by T cells. You can read about the first efforts to develop BiTEs, by CRI scientific advisory council member Gert Riethm├╝ller, in our journal Cancer Immunity.

T cells taken outside of the body and genetically engineered to bind to CD19 along with a T cell activating signal—called chimeric antigen receptors, or CARs—have produced dramatic regressions in patients with chronic lymphocytic leukemia and acute lymphoblastic leukemia in recent years. Read our past blog posts "More Good News For Immunotherapy Patients" (3/27/2013) and "A Game-Changing Moment in Cancer" (12/13/2012) for more information about these breakthroughs.

The idea of classifying different cell functions via their surface markers was first conceived by CRI’s founding scientific and medical director Lloyd J. Old, when he and his longtime colleague Ted Boyse discovered and characterized the Ly antigen system. CRI-funded fellows, including Dr. Eiichi Nakayama, with Dr. Old and others, further characterized CD8+ (then Ly2) cells as the immune cells endowed with cell-killing function. Based on their work, a uniform system of classifying CD antigens was proposed and established in 1982. Today, more than 320 unique CD antigens/antigen clusters have been identified. Although it may take some time, it is likely that many of these as-yet-fully-understood molecules will become promising new targets for immunotherapy in the future. Stay tuned.
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