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Cancer Immunotherapy: Beyond Checkpoint Blockade
Michael Dougan1,2, Glenn Dranoff3, Stephanie K Dougan2,4
1Division of Gastroenterology and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Abstract:
Blocking antibodies to the immune checkpoint receptors or their ligands have revolutionized the treatment of diverse malignancies. Many tumors are recognized by adaptive immunity, but these adaptive responses can be inhibited by immunosuppressive mechanisms within the tumor, often through pathways outside of the currently targeted checkpoints. For this reason, only a minority of cancer patients achieve durable responses to current immunotherapies. Multiple novel approaches strive to expand immunotherapy's reach. These may include targeting alternative immune checkpoints. However, many investigational strategies look beyond checkpoint blockade. These include cellular therapies to bypass endogenous immunity and efforts to stimulate new adaptive antitumor responses using vaccines, adjuvants, and combinations with cytotoxic therapy, as well as strategies to inhibit innate immune suppression and modulate metabolism within the tumor microenvironment. The challenge for immunotherapy going forward will be to select rational strategies for overcoming barriers to effective antitumor responses from the myriad possible targets.
Insights
Current cancer immunotherapies targeting immune checkpoints benefit only a few patients. New strategies are needed to overcome tumor-induced immunosuppression and expand durable responses for more cancer patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint blockade has transformed cancer treatment but benefits a minority of patients.
- Tumors employ immunosuppressive mechanisms, often beyond current targets, limiting immunotherapy efficacy.
- Developing novel strategies is crucial to enhance antitumor responses and achieve durable remissions.
Purpose of the Study:
- To review emerging strategies for overcoming resistance to cancer immunotherapy.
- To explore novel targets and therapeutic approaches beyond current immune checkpoint inhibitors.
- To identify rational methods for enhancing adaptive antitumor immunity.
Main Methods:
- Literature review of current and investigational cancer immunotherapy strategies.
- Analysis of mechanisms of tumor-induced immunosuppression.
- Synthesis of data on alternative immune checkpoints, cellular therapies, vaccines, and combination approaches.
Main Results:
- Current immunotherapies achieve durable responses in a limited patient population.
- Numerous novel strategies are under investigation, including alternative checkpoint targets, cellular therapies, vaccines, and metabolic modulation.
- Overcoming innate immune suppression and tumor microenvironment barriers are key challenges.
Conclusions:
- Expanding immunotherapy's reach requires addressing diverse immunosuppressive mechanisms.
- Rational selection of novel strategies is essential for improving patient outcomes in cancer immunotherapy.
- Future research should focus on combination therapies and targeting non-checkpoint pathways to overcome treatment resistance.
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