Adaptive immune resistance is a process in which the cancer changes its phenotype in response to a cytotoxic or proinflammatory immune response, thereby evading it. This adaptive process is triggered ...by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T-cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1-blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies.
Several new immunotherapy strategies to treat cancer are based on inhibiting processes through which cancer adapts and evades from an immune response. Recognizing the specific adaptive resistance mechanisms in each case is likely to allow the personalized development of immunotherapies tailored to block how a particular cancer protects itself from the immune system.
The treatment of cancer by harnessing immune responses has long been pursued. Efforts to turn on the immune system against cancers with inactivated tumor vaccines or intratumor injections of ...bacterial products to induce local inflammation and recruit an antitumor immune response have led to anecdotal successes. Increasing knowledge about how the immune system is activated, coupled with advances in recombinant DNA technology, has allowed the clinical testing of immune-stimulating cytokines such as interferons and interleukins. These trials have led to a low frequency of durable tumor responses in selected cancers such as melanoma and renal-cell carcinoma at the expense of . . .
James Allison, winner of this year's Lasker–DeBakey Clinical Medical Research Award, did seminal work that has led to checkpoint-blockade immunotherapy, arguably the most exciting advance made in ...cancer treatment in recent years.
After mapping out the molecular mechanisms of T-cell antigen recognition, regulation, and function in the 1980s and 1990s, immunologist James P. Allison hypothesized that blocking negative immune regulators (checkpoints) would give the human immune system the power to fight cancer. His testing of this hypothesis in preclinical models led to the clinical development of a new generation of active agents for cancer treatment. In some subgroups of patients, unleashing native immune-system cells to fight cancer now provides a realistic chance of long-term remission. For this seminal work, Allison, a professor at the M.D. Anderson Cancer Center in Houston, has won . . .
Cancer immunotherapy using checkpoint blockade Ribas, Antoni; Wolchok, Jedd D
Science (American Association for the Advancement of Science),
03/2018, Letnik:
359, Številka:
6382
Journal Article
Recenzirano
Odprti dostop
The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a ...variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti-PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which ...leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response. Finally, a tumor that is unable to express PD-L1 because of a genetic event will always be negative for PD-L1 on cancer cells.
Highlights • First FDA approvals for anti-PD-1 antibodies for patients with metastatic melanoma. • Promising response from ongoing clinical trials with several anti-PD-1/L1 antibodies. • Need to ...define bio-markers to predict response from anti-PD-1/L1 antibody therapy. • Multiple checkpoint inhibitors that are under pre-clinical development. • Future studies will identify ideal combinations of checkpoint inhibitors.
Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab ...demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. These tumor responses are mediated by the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) as demonstrated in patient-derived tumor biopsies. Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4-mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.
Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. ...However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents.
Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an ...improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
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