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Prior to joining the Whitehead Institute, Dr. Hidde Ploegh taught at Harvard Medical School, where he headed the school's immunology program. Previous to that, Ploegh was a Professor of Biology at MIT, working in the Center for Cancer Research (now David H. Koch Institute for Integrative Cancer Research).
Dr. Ploegh introduced the immune system, or human microbial defense system, by stating that we have three levels of protection:
First line: mechanical defense - skin and chemical defenses (ciliary clearance, low stomach pH, and lysozymes in tears and saliva).
Second line: innate immunity - is antigen-nonspecific defense mechanisms that a host uses immediately, or within several hours after exposure to almost any microbe. This immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection. This includes antibodies, natural killer cells (NK), and macrophage and complement system. Innate immunity plays an essential role in activating the adaptive immune response.
Innate immunity can be subdivided into two categories:
- Humoral immunity: involves the production of antibody molecules in response to an antigen and is mediated by B-lymphocytes.
- Cell-mediated immunity: involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen and is mediated by T-lymphocytes.
Third line: adaptive immunity is antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This immunity one develops throughout life and it includes T cells (helper, cytotoxic, suppressor and memory T cells), B cells (effector and memory), dendritic cells, antigens, and cytokines.
Adaptive immunity also can be subdivided into two categories:
- Humoral immunity: involves the production of antibody molecules in response to an antigen and is mediated by B-lymphocytes.
- Cell-mediated immunity: involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen and is mediated by T-lymphocytes.
Our immunity is now believed to be achieved through the integration of innate and adaptive immunity. Failure of either of these systems increases our chance of developing an infection. Since our innate immunity is rather limited, pathogens can rapidly evolve and avoid detection by simply altering the targeted microbial molecules. "However, the innate immune system has evolved to recognize either microbial components that are essential for the viability and virulence of microbes and are thus less prone to modifications, or common biological consequences of infection."
There are at least three broad strategies used by the innate immune system to recognize invading microorganisms.
1) Detecting 'microbial non-self' (i.e. pathogen-associated molecular patterns (PAMPs))
2) Detecting common metabolic consequences of cell infection or injury (i.e. damage associated molecular patterns (DAMPs))
3) Detecting 'missing self'
This is your basic overview of the immune system, a very complex process where numerous scientists have done research, with the goal of increasing our understanding of its mechanisms.
Jim Allison, PhD, chair of The University of Texas MD Anderson Cancer Center Department of Immunology, studied the biology of the immune system's T cells and discovered how cancer cells are able to evade attack by the immune system. His research helped to develop the first therapy that enhanced the body's immune response to cancers.
In the 1990s, Dr. Allison's study in mice demonstrated that CTLA-4, a molecule expressed on T cells, blocks the body's natural immune response. An antibody he developed against CTLA-4 inhibits tumor growth in mice, and has evolved into Ipilimumab, a successful treatment for advanced-stage melanoma in humans.
Dr. Allison's seminal scientific discoveries include:
* The T cell antigen receptor used by T cells to bind to and recognize antigens.
* That T cells require a second signal to launch a response after they've bound to an antigen. B7 molecules on presenting cells must engage a surface molecule called CD28 on the T cell.
* The immune-inhibiting molecule called CTLA-4 inhibits activated T cells and protects normal tissue from attack. CTLA-4 apparently also protects cancer cells from attack.
Ipilimumab, a monoclonal antibody developed from Dr. Allison's research, blocks CTLA-4, which allows the immune system, over time, to recognize and attack cancer cells. Ipilimumab is designed to find and lock into (like lock and key configuration specific antigen to) CTLA-4, a protein receptor that down regulates the immune system and protects the tumor. Ipilimumab blocks the effects of the negative T-cell regulator CTLA-4 which then, in turn, augments T-cell responses to tumor cells. Ipilimumab is thought to boost the immune response against melanoma cells in the body. This new approach is called immune checkpoint blockade.
Combining targeted therapy with checkpoint blockade can turn cancer's genomic instability, which it uses to build resistance to drugs, against it, Dr. Allison explains.
"The idea here is when you kill tumor cells with the targeted drug you cause inflammatory cell death, which introduces lots of new antigens into the system. Combine checkpoint blockade with the drug and you reveal those antigens as targets (for the immune system) and, in effect, turn one drug into many drugs." said Allison.
The results of the clinical trial for ipilimumab: The median overall survival was 10.0 months among patients receiving ipilimumab plus glycoprotein 100 (gp100) peptide vaccine, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). This is significant for cancer survival. The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). Yervoy (ipilimumab) was approved by the U.S. Food and Drug Administration in May 2011.
"Genomic instability is a hallmark of cancer cells so they should be prime targets for the immune system," Dr. Allison has commented. "Cancer cells evade this attack, and Allison's T cell discoveries provide insight into why."
What lead to Dr. Allison's work in immune checkpoint blockade was "The fundamental discovery by Drs. Mossman and Coffman of the specific types of T cells that helped either cellular or humoral (antibody-mediated) immunity revolutionized our understanding of how the immune system works, and led to major advances in designing therapies for infectious, inflammatory and allergic diseases and in vaccine design," comments Dhaval Patel, Head, NIBR Europe and Global Head of Autoimmunity, Transplantation and Immunology.
While working together in the 1980s at DNAX Research Institute in Palo Alto, CA, Drs. Mossman and Coffman determined the distinct functions of two T-helper cell subsets - with Th1 playing a major role in cellular immunity critical for resistance to infections, whereas Th2 cells can induce allergic diseases. They also found that dysregulation of Th1 and Th2 cell functions were implicated in many immunological diseases.
All three eminent scientists received the Prestigious Novartis Prizes for Immunology at the 15th International Congress of Immunology in Milan, Italy in August 2013. Novartis Prizes for Immunology are awarded for groundbreaking research into the biology of immune system T cells that has advanced the prevention and treatment of a variety of diseases.
Dr. Allison joins MD Anderson to play a vital role in their new program called Moon Shots Program to dramatically accelerate the pace of converting scientific discoveries into clinical advances that reduce cancer deaths.
"The main reason for coming to MD Anderson is the opportunity offered by a clinical community that's open to using immunological approaches to treat cancer combined with other therapies," Allison said.
"We plan to build a large platform where basic scientists interested in mouse models of cancer work side-by-side with physician-scientists who treat patients to analyze tissues from those patients and truly understand the mechanisms involved," Allison said. "We can accelerate the transition of new combinations of drugs into the clinic beyond phase I clinical trials and broaden our focus beyond melanoma and prostate cancer to other types of cancer."
"We all know that no single drug will cure cancer. I think this is where we'll start getting cures, or at least long-term survival of patients. There's lots of enthusiasm for this approach at MD Anderson and I'm really excited about it," Allison said.
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