A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization
Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This “immune enhancement” strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed “immune normalization,” which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.
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A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization
Re: A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization
Main Text
Introduction
Successful generation of a T cell-mediated immunity to eliminate antigen includes but it is not limited to the following steps: (1) tumor-antigen uptake and processing by antigen-presenting cells (APCs), (2) migration of APCs to lymphoid organs, (3) tumor-antigen presentation fine-tuned by co-stimulation and co-inhibitory signals that regulate the activation of tumor-specific naive T cells to become effector T cells in lymphoid organs, (4) the regression of tumor-specific effector T cells from lymphoid organs into peripheral blood and trafficking to tumor tissues, (5) tumor-antigen recognition and tumor lysis, and (6) death of effector T cells and the generation of tumor-specific memory T cells. Based on the understanding of these cellular and molecular mechanisms, various types of immunotherapies were developed to “push” immune activation through the modulation of general regulatory and/or activatory mechanisms governing these steps to improve antitumor immune responses in quantity and/or quality. This general approach aims to activate and increase the immune response, and we have termed this as “enhancement immunotherapies.”
However, cancer does not simply grow to race with the development of immune responses, but rather actively employs various tactics to delay, alter, or even stop antitumor immunity. These tactics, collectively termed “immune evasion mechanisms,” often defeat intrinsically developed antitumor immunity, leading to a failure in the control of tumor growth. These mechanisms develop continuously during the progression of cancer and become more diverse and complex in late-stage cancers. New approaches to improve the immune response against cancer consist of blocking these immune evasion mechanisms. One of the first and most characterized immune evasion mechanisms is the programmed cell death (PD) pathway. This pathway inhibits an effector T cell antitumor immune response when it is upregulated in the tumor microenvironment, and therapies blocking this pathway have proven effective at improving an antitumor immune response against multiple tumor types. This approach is conceptually different from the previous enhancement approach. While enhancement approaches are designed based on the knowledge of the general activation process, anti-PD therapy exploits new knowledge based on immune evasion mechanisms. Furthermore, while in the enhancement approach, we assume that the general mechanisms of immune system activation are always the same, anti-PD therapy first requires a careful study of the tumor microenvironment (TME) to identify that the PD pathway is upregulated, making this therapy more “personalized.” We believe that this approach represents the first of an emerging group of strategies in the future of cancer immunology research and will expand as we understand better mechanisms of immune escape. Because this new approach aims to restore a lost antitumor immunity, we have termed it “normalization cancer immunotherapy.”
Introduction
Successful generation of a T cell-mediated immunity to eliminate antigen includes but it is not limited to the following steps: (1) tumor-antigen uptake and processing by antigen-presenting cells (APCs), (2) migration of APCs to lymphoid organs, (3) tumor-antigen presentation fine-tuned by co-stimulation and co-inhibitory signals that regulate the activation of tumor-specific naive T cells to become effector T cells in lymphoid organs, (4) the regression of tumor-specific effector T cells from lymphoid organs into peripheral blood and trafficking to tumor tissues, (5) tumor-antigen recognition and tumor lysis, and (6) death of effector T cells and the generation of tumor-specific memory T cells. Based on the understanding of these cellular and molecular mechanisms, various types of immunotherapies were developed to “push” immune activation through the modulation of general regulatory and/or activatory mechanisms governing these steps to improve antitumor immune responses in quantity and/or quality. This general approach aims to activate and increase the immune response, and we have termed this as “enhancement immunotherapies.”
However, cancer does not simply grow to race with the development of immune responses, but rather actively employs various tactics to delay, alter, or even stop antitumor immunity. These tactics, collectively termed “immune evasion mechanisms,” often defeat intrinsically developed antitumor immunity, leading to a failure in the control of tumor growth. These mechanisms develop continuously during the progression of cancer and become more diverse and complex in late-stage cancers. New approaches to improve the immune response against cancer consist of blocking these immune evasion mechanisms. One of the first and most characterized immune evasion mechanisms is the programmed cell death (PD) pathway. This pathway inhibits an effector T cell antitumor immune response when it is upregulated in the tumor microenvironment, and therapies blocking this pathway have proven effective at improving an antitumor immune response against multiple tumor types. This approach is conceptually different from the previous enhancement approach. While enhancement approaches are designed based on the knowledge of the general activation process, anti-PD therapy exploits new knowledge based on immune evasion mechanisms. Furthermore, while in the enhancement approach, we assume that the general mechanisms of immune system activation are always the same, anti-PD therapy first requires a careful study of the tumor microenvironment (TME) to identify that the PD pathway is upregulated, making this therapy more “personalized.” We believe that this approach represents the first of an emerging group of strategies in the future of cancer immunology research and will expand as we understand better mechanisms of immune escape. Because this new approach aims to restore a lost antitumor immunity, we have termed it “normalization cancer immunotherapy.”
Debbie