Immunotherapy: It is not just for cancer anymore

Undoubtedly, one of themost remarkable recent advances inmedicine has been the efficacy of the “checkpoint inhibitors” to improve survival in cancer patients. The enormous impact of checkpoint inhibitors is evidenced by the fact that these drugs are now approved for at least 8 different types of malignancies and well over 50,000 patients have been treated with these new immunoadjuvants, many who have failed all other conventional therapies. The term “checkpoint inhibitors” was first popularized by Drew Pardoll and describes inhibitory pathwayshardwired into the immune system that are crucial formaintaining self-tolerance.1 Probably the2most commonly studied have been the PD-1/PD-L1,PD-L2 and CTLA4/CD80,CD86 inhibitory systems. Their primary function is to attenuate the magnitude and duration of immune responses in order to minimize collateral tissue damage during a host immune response. Many tumors have corrupted these systems to obtain protective immunity from host tumor cell killing. Successful interventions with anti-CTLA4 (ipilimumab) and to a greater extent, anti-PD-1 (nivolumab, pembrolizumab) have clearly demonstrated the success of blocking these networks and unleashing host immunity in many patients with actively growing tumors. Thus, checkpoint inhibitors, in contrast to most other cancer drugs, act by improving the ability of the patient's own intrinsic immunity to eradicate the cancer cells. These treatments have revolutionized cancer treatment and have heralded in the age of precision medicine and immunotherapies. It has not gone unnoticed that many of the immunological characteristics of an actively growing tumor are shared by several non-cancer acute and chronic inflammatory diseases.2 Burns, trauma, and sepsis represent some of the most severe inflammatory challenges to the host. Although early mortality to all three has dramatically improved over the past decade, many of the survivors suffer long-term consequences consistent with immune suppression, such as nosocomial infections and reactivation of latent viral infections. Severe burns in particular have been associated with persistent inflammation and loss of host protective immunity that can last for periods extending beyond a year.3 Patients with severe burns (>15% body surface area) are uniformly colonized by both nonpathogenic and pathogenic bacteria, and commonly develop sepsis within the first 14daysof admission. This increased susceptibility to sepsis is undoubtedly due to destruction of the cutaneous barrier to infection, but is also exacerbated by reduced adaptive and innate immune responses. In fact, the similarities between the patient with burn injuries andwith active growing tumors is not limited to host protective immunity, but also includes persistent inflammation, anemia, lean tissue wasting, and increased energy expenditure. From amore mechanistic point of view, many of these cancers aswell as burns, sepsis, and severe trauma show dramatic changes in bone marrow function with increased proliferation and release of immature myeloid cells at the expense of lymphopoiesis and hematopoiesis. Many of these immature myeloid populations express high levels of PD-L1 and its receptor, PD-1, and have been implicated in their increased activity. Although the efficacy of checkpoint inhibitors is well established in oncology, there is a growing body of evidence that checkpoint inhibitors may be effective in many infectious disorders as well.4 In fact, themostwidely used checkpoint inhibitor, programmed cell death 1 (PD-1), was first described in a murine viral infectious model.5 Administration of anti-PD-1 antibody to mice chronically infected with lymphocytic choriomeningitis virus restored CD8 T cell function and decreased viral load. Subsequent investigations have shown that checkpoint inhibitors improve immunity and increase survival in bacterial and fungal models of sepsis.6 Significantly, studies of peripheral blood mononuclear cells from patients with sepsis have shown that treatment with anti-PD-1 antibody prevents sepsis-induced apoptotic death of CD4+ and CD8+ T cells and restores production of the key cytokines IFNγ and IL-2. The current study by Patil and colleagues represents an important addition to the expanding data supporting use of checkpoint inhibitors in burns and bacterial sepsis.7 Sepsis is the most common cause of death in burn patients who survive the first 24– 48 h after injury. The authors documented that a single dose of an antibody directed against the ligand for PD-1, that is, anti-PD-L1, improved survival in a mouse model of burn injury with sepsis. AntiPD-L1 antibody was protective against both gram-positive bacteria (Staphylococcal aureus) and Gram negative bacteria (Pseudomonas aeruginosa). Both pathogens are major causes of morbidity and mortality in burn patients as well as in the general intensive care unit population. P. aeruginosa is classified as one of the multidrug resistant pathogens in which only a few drugs remain active and effective against this highly lethal pathogen. Despite a concern that blocking the actions of PD-L1 could release a “cytokine or genomic storm,” plasma inflammatory cytokines were generally reduced, more consistent with the reduced bacteremia and improved survival. Rather, by improving infection control, as documented by the reduced bacteremia, the magnitude of the inflammatory response and the degree of organ injury were actually improved.