Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally
1Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.
Background:
Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well-characterized at preclinical and clinical levels.
Patients And Methods:
We used PubMed and Google Scholar searches to identify key articles published reporting preclinical and clinical studies investigating CTLA-4 and PD-1/PD-L1, frequently cited review articles, and clinical studies of CTLA-4 and PD-1/PD-L1 pathway inhibitors, including combination therapy strategies. We also searched recent oncology congress presentations and clinicaltrials.gov to cover the most up-to-date clinical trial data and ongoing clinical trials of immune checkpoint inhibitor (ICI) combinations.
Results:
Inhibiting CTLA-4 and PD-1 using monoclonal antibody therapies administered as single agents has been associated with clinical benefit in distinct patient subgroups across several malignancies. Concurrent blockade of CTLA-4 and components of the PD-1/PD-L1 system using various schedules has shown synergy and even higher incidence of durable antitumor responses at the expense of increased rates of immune-mediated adverse events, which can be life-threatening, but are rarely fatal and are reversible in most cases using established treatment guidelines.
Conclusions:
Dual immune checkpoint blockade has demonstrated promising clinical benefit in numerous solid tumor types. This example of concurrent modulation of multiple components of the immune system is currently being investigated in other cancers using various immunomodulatory strategies.
Insights
Dual immune checkpoint blockade, targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1)/PD-L1, shows durable antitumor responses in various cancers, with manageable immune-related adverse events.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- Cancers evade immune surveillance through central and peripheral immune tolerance mechanisms.
- Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1)/PD-L1 are key co-inhibitory immune checkpoint molecules.
- Early cytokine therapies showed moderate clinical benefit for some cancers.
Purpose of the Study:
- To review preclinical and clinical evidence for CTLA-4 and PD-1/PD-L1 pathway inhibitors.
- To evaluate combination therapy strategies for immune checkpoint inhibitors (ICIs).
- To assess current clinical trial data and ongoing investigations of ICI combinations.
Main Methods:
- Searched PubMed and Google Scholar for relevant preclinical and clinical studies.
- Included frequently cited review articles and clinical studies of ICI pathway inhibitors.
- Reviewed recent oncology congress presentations and clinicaltrials.gov for up-to-date data.
Main Results:
- Single-agent CTLA-4 and PD-1 inhibition yielded clinical benefit in specific cancer types.
- Concurrent blockade of CTLA-4 and PD-1/PD-L1 demonstrated synergistic antitumor responses.
- Combination therapy increased durable responses but also immune-mediated adverse events, generally manageable.
Conclusions:
- Dual immune checkpoint blockade shows significant promise across multiple solid tumor types.
- This strategy of modulating multiple immune system components is under active investigation.
- Further research is exploring various immunomodulatory strategies for broader cancer treatment.
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