However, in large-scale use in patients with solid tumors, ICBT remains ineffective, for two main reasons: adaptive resistance and intrinsic resistance. By inhibiting the immune checkpoints that suppress T-cell activation, immune checkpoint blockade therapy (ICBT) has resulted in a response rate as high as 40% in melanoma patients, with some durable effects ( 1, 2). Since 2011, blockers of inhibitory immune checkpoints, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), have been approved by the FDA to treat solid tumors, thanks to their exciting success in clinical trials. Unlike the classic mAbs that target oncogenic pathways, such as HER2 to kill tumor cells, the mAbs of inhibitory immune checkpoints stimulate the functions of T cell. Immune checkpoints are critical molecules that either turn up or turn down the T-cell–stimulatory signals of the immune response. Progress in the new personalized ICBT strategies will expand the reach of immunotherapy to more cancer types, thus enabling more patients to benefit. Translation of those preclinical findings to the clinical arena will help generate personalized ICBT strategies that target tumor-specific resistance mechanisms. With our evolving understanding of intrinsic resistance, people have successfully tested, in preclinical models, treatments targeting specific resistance mechanisms to sensitize ICBT-resistant tumors.
Low tumor immunogenicity and a strong immunosuppressive tumor microenvironment cause significant intrinsic resistance to ICBT.
The properties of the tumor microenvironment control T-cell infiltration, distribution, and function in tumor tissues. Mechanistically, the number of mutations determines tumor immunogenicity. The efficacy of ICBT is tightly modulated by the function of each step in the antitumor immunity cycle. However, intrinsic resistance (i.e., insensitivity of the tumors to therapy) remains a daunting challenge.
Immune checkpoint blockade therapy (ICBT), which blocks negative immune-activating signals and maintains the antitumor response, has elicited a remarkable clinical response in certain cancer patients.
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