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Published on: February 5, 2020
Why has immune "checkpoint" therapy failed in most clinical trials?
Xuan Yang1, Lieping Chen2,3,4
1Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
Abstract:
Cancer immunotherapy targeting the PD-1/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other 'checkpoint inhibitors' targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance-but not redundancy-of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.
Insights
Despite successes with PD-1/PD-L1 pathway inhibitors, other checkpoint inhibitors like TIM-3 and TIGIT show limited benefit. This review explores reasons for these failures and suggests a strategic path forward for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Cancer immunotherapy utilizing PD-1/PD-L1 pathway blockade has achieved significant clinical success in various cancers.
- Development of other immune checkpoint inhibitors targeting molecules such as TIM-3 and TIGIT has yielded limited clinical benefits, even in combination therapies.
Purpose of the Study:
- To explore key hypotheses explaining the differential therapeutic success of immune checkpoint inhibitors.
- To provide a biologically informed strategy for advancing cancer immunotherapy.
Main Methods:
- Review of select evidence and scientific literature.
- Exploration of three core hypotheses regarding checkpoint inhibitor efficacy.
- Analysis of tumor microenvironment (TME) immune evasion mechanisms.
Main Results:
- Hypothesis 1: Many checkpoint targets lack tumor-specific immunosuppressive functions.
- Hypothesis 2: Immune evasion mechanisms in the TME are dominant but not redundant.
- Hypothesis 3: Acquired resistance emerges during therapy.
Conclusions:
- The limited success of novel checkpoint inhibitors may stem from their targets' biology and the complex TME.
- A more strategic approach, considering tumor-specific immunosuppression, TME dynamics, and resistance mechanisms, is crucial for future cancer immunotherapy development.
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