Inhibitors of immune checkpoints-PD-1, PD-L1, CTLA-4-new opportunities for cancer patients and a new challenge for internists and general practitioners.

The treatment of cancer patients with immune checkpoint inhibitors (ICI) (anti-CTLA-4, anti-PD-1, anti-PD-L1, combined therapy anti-PD-1/PD-L1 with anti-CTLA-4) has without doubt been a significant breakthrough in the field of oncology in recent years and constitutes a major step forward as a novel type of immunotherapy in the treatment of cancer. ICIs have contributed to a significant improvement in the outcome of treatment and prognosis of patients with different types of malignancy. With the expansion of the use of ICIs, it is expected that caregivers will face new challenges, namely, they will have to manage the adverse side effects associated with the use of these drugs. New treatment options pose new challenges not only for oncologists but also for specialists in other clinical fields, including general practitioners (GPs). They also endorse the need for taking a holistic approach to the patient, which is a principle widely recognized in oncology and especially relevant in the case of the expanding use of ICIs, which may give rise to a wide variety of organ complications resulting from treatment. Knowledge and awareness of the spectrum of immune-related adverse events (irAEs) will allow doctors to qualify patients for treatment more appropriately, prevent complications, correctly recognize, and ultimately treat them. Additionally, patients with more non-specific symptoms would be expected, in the first instance, to consult their general practitioners, as complications may appear even after the termination of treatment and do not always proceed in line with disease progression. Dealing with any iatrogenic complications, will not only be the remit of oncologists but because of the likelihood that specific organs may be affected, is likely to extend also to specialists in various fields of internal medicine. These specialists, e.g., endocrinologists, dermatologists, pulmonologists, and gastroenterologists, are likely to receive referrals for patients suffering from specific types of adverse events or will be asked to provide care in cases requiring hospitalization of patients with complications in their field of expertise. In view of these considerations, we believe that there is an urgent need for multidisciplinary teamwork in the treatment of cancer patients undergoing immunotherapy and suffering the consequent adverse reactions to treatment.

In vivo blockade of the programmed cell death-1 pathway using soluble recombinant PD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit.

The programmed cell death-1 (PD-1)/programmed cell death ligand-1 pathway has been shown to limit cell-mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell polyfunctionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD-1 fused to a macaque Ig-Fc (rPD-1-Fc) in SIVmac239-infected rhesus macaques during the early chronic phase of infection, either alone or in combination with antiretroviral therapy. In vitro blockade showed improvement of Ag-specific CD4(+) and CD8(+) T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-d blockade in culture was beneficial for both gag-specific CD4(+) and CD8(+) T cells based on proliferation and dual cytokine production. Although the in vivo administration of rPD-1-Fc induced enhanced SIV-specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of antiretroviral therapy interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001(+) monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9(+) CD8(+) T cells in the blood and rectal mucosa and polyfunctionality of GagCM9(+) CD8(+) T cells in blood. In conclusion, however, our data suggest that PD-1/programmed cell death ligand-1 blockade using soluble rPD-1-Fc instead of anti-PD-1 mAb, although effective in rescuing the effector function of SIV-specific CD4(+) and CD8(+) T cells during the early chronic phase of infection, has limited clinical benefit.