Treating tumors with immune checkpoint inhibitors: Rationale and limitations

Abstract

Immune checkpoints are essential for preventing immunopathology but can also obstruct anti-tumor immune responses. Recent medical advances in blocking these mechanisms have therefore opened promising avenues in the treatment of cancer. Various blocking antibodies targeting the immune checkpoints programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now approved for human use. This review summarizes the properties of PD-1 and CTLA-4 in physiological and tumor settings, and examines the treatment efficacy, side effects and biomarkers of their inhibitors. Future avenues in the application and development of immune checkpoint inhibitors for the treatment of cancer are also explored.

The Nobel Prize in Physiology or Medicine 2018 was awarded to Cancer Therapy by Inhibition of Negative Immune Regulation

“…I herein introduce briefly my previous report with some modification [6] . Immune checkpoints inhibitors (ICIs) have and Kabashima described in their review article [7] , mortality among advanced stage patients and the frequency of treatment-related adverse events remain high with current treatment. And, it is also noteworthy that unexpected immune related adverse effects (irAEs) appear, even when it becomes better to be administered to many cancer patients [8] .…”

“…Unfortunately, the mechanisms of endocrine irAEs by ICIs, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. However, appropriate uses and index setting related to prognosis are being studied in many fields such as dermatology [9] and other organs [6,7] .…”

Immune checkpoint inhibitors and irAEs

“…They significantly improved disease outcome in a number of cancer patients by boosting anti-tumor immune responses. As Seidel et al described in their review article [3] , mortality among advanced stage patients and the frequency of treatment-related adverse events remain high with current treatment.…”

“…In addition, the need for predictive markers of treatment efficacy and the development of improved treatment avenues therefore remain as acute as ever [3] . sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab [5] .…”

Cancer vaccine therapy based on peptides

“…One type of immunotherapy is immune checkpoint inhibitors using humanized monoclonal antibody (mAb) specific to cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death protein 1 (PD-1) or its ligand PD-L1. These immune checkpoints are involved in the immune suppression of tumor-reactive T cells, and blockades of these molecules by antibody would enhance T-cell-mediated immune response to tumors [4,5] . Adoptive immunotherapy, such as chimeric antigen receptor T-cell (CAR-T) therapy, attracts rising attention for its remarkable clinical effects, especially for patients with hematological cancer [6][7][8][9][10] .…”