dysregulation is likely partly due to the malfunction of Tregs, something seen in various autoimmune diseases. Tregs are a key player in maintaining immune homeostasis and modulating immune function. Babies born without Tregs develop massive systemic autoimmunity, which can be lethal unless Tregs are replenished through a bone marrow transplant. Tregs are critical because they have multifaceted functions: They make several immunoregulatory factors and express proteins on their cell surfaces that shut down the immune response and educate other cells to suppress it. These proteins include several checkpoints like CTLA-4 and programmed cell death protein-1 ( PD-1 ) . Trying to replicate the polypharmaceutical activity of Tregs with a single drug is difficult unless sledgehammers like immunosuppressives are used, which can increase the risk of infection and cancer. Tregs not only shut down inflammation directly but also recruit other cells, turn them into regulatory cells and produce factors that can help regenerate and repair damaged tissues, thus amplifying their effect. The first experiments on immune tolerance occurred in the 1950s, but the field lagged for decades after. What ’ s it like watching progress accelerate recently? There wasn ’ t much progress for 30 years after Sir Peter Medawar ’ s Nobel Prize-winning research on acquired immunological tolerance in newborn mice was published in 1951. The field was born, but many questions remained. The first major advance was the development of broad immunosuppressives to block the immune response. There was hope that tolerance would “ evolve ” over time. Some approaches were more successful than others. For example, bone marrow transplantation wipes out the entire immune system and lets the body rebuild it. But this broad therapeutic approach can often lead to graft-versus-host disease, where the “ new ” immune system attacks the body. Other treatments target the end-stage mediators of immunity. Broad immunosuppressives such as anti-TNF ( tumor necrosis factor ) or anti-CD20 monoclonal antibodies given for long periods of time can sometimes allow drug withdrawal. Most often, the disease requires life-long drug use, often at the expense of increased risk of infection or cancer. I was fortunate to direct the Immune Tolerance Network where several new approaches to induce immune tolerance were pioneered including introducing peanuts during the first year of life to prevent peanut allergy. This work built on Dr. Medawar ’ s research from the 1950s. Another example was the development of an anti-CD3 monoclonal antibody to prevent type 1 diabetes ( T1D ) . The first monoclonal antibody drug, orthoclone OKT3, was FDA-approved in the 1980s to reverse kidney transplant rejection. The drug had some success but with significant side effects and was not durable. It took 30 years to understand all the complexities of achieving tolerance with drugs like OKT3. It led to the approval of a next-generation anti-CD3 monoclonal antibody, teplizumab, to treat at-risk individuals before they develop autoimmune T1D. It felt like vindication for the decades of hard work by so many people developing this potentially tolerogenic drug. So, are we there yet? No! Only a subset of individuals achieve life-long protection from developing T1D. Much work is left to harness the potential of immune tolerance — the holy grail for immunotherapy. We have ways to go to create scalpels instead of sledgehammers.
“ Immune tolerance is the holy grail; we are not there yet. ”
For decades, cancer seemed like a death sentence. How has immunology changed the cancer-treatment landscape? Cancer therapy has come a long way since the early days of radiation and chemotherapy, poisons that we hoped would kill more tumor cells than healthy tissues. We have new drugs that target cancers more specifically. Different approaches are used, too. Instead of putting chemo in the body systemically, drugs are being developed that arm tumor-specific antibodies that only kill the tumor and leave normal tissues unscathed. That ’ s gigantic. Turning cancers into chronic diseases is a race. You kill the cancer off with one drug, but a few of those cells mutate and come back, so you use another drug. Checkpoint inhibitors changed the game as unleashing the immune system meant that tumors “ could run but could not hide. ” The mutations that allowed for an escape from the chemo- and targeted therapies that often beat up the immune system can be recognized by immune cells energized by the anti-PD-1, anti-CTLA-4 or other checkpoint inhibitors. These drugs were found to be even more effective when given as first-line therapies when there is a high tumor burden, the immune system is more intact, and the tumor is most immunogenic. Cell therapy and immunotherapy could create living systems that fight cancer continuously. They rely on mutated proteins expressed by the tumor that can be recognized by the immune system, which sees them as foreign. Mutations are immunogenic and prime the immune system to recognize and kill cancer cells, generating a much more profound effect. This is where checkpoint inhibitors come in. However, there are clear examples of failure where the immune system is not activated despite a significant mutational load. Much of this is due to the tumor microenvironment, where immunosuppressive factors and cells shut down local immunity. Tregs play a key role in this leading to new drugs to eliminate this population. In addition, more non-specific approaches like radiation and chemotherapy are now being repurposed to promote local immunogenic cell death to attract and activate the immune system. Another approach uses killer T cells as immunotherapies. Researchers have developed novel killer cells with chimeric antigen receptors ( CARs ) to recognize tumor-expressed antigens in settings where mutational load is insufficient to promote tumor immunity. These engineered killer T cells are injected into patients to mediate tumor destruction. Dr. Carl June successfully treated the first pediatric patient in 2012 using genetically engineered T cells in a patient with blood cancer. It was a very gratifying moment in the field, giving hope for the future. The patient, Emily Whitehead, whom I have known since she was five, is still in remission 12 years later. However, even killer CAR T cell therapy is not a panacea, and there has been less success in other
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