An Overview and Update on Immune Checkpoint Inhibitors in Cancer Treatment

OVERVIEW

The word revolutionary is used frequently to describe the advent of Immune Checkpoint Inhibitors (ICIs) in cancer treatment over a decade ago. The National Cancer Institute (NCI) defines ICIs as drugs that block proteins called checkpoints that are made by immune system cells, such as T cells, and some cancer cells. The checkpoints function to keep immune responses from being too strong but sometimes can keep T cells from killing cancer cells. When these checkpoints are blocked, T cells can kill cancer cells better. Examples of checkpoint proteins found on T cells or cancer cells include Programmed Death-1 (PD1), Programmed Death-Ligand 1 (PDL1) and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA4).¹
 
Since the FDA approved ipilimumab, the first monoclonal antibody (MAB) blocking the immune checkpoint CTLA4, in 2011, anti-PD1/PDL1 MABs have become some of the most widely prescribed anticancer treatments. These ICIs are now used as single agents or in combination with chemotherapies as first or second lines of therapy for approximately 50 cancer types. There are also over 3000 active clinical trials evaluating T cells modulators.² The revolutionary designation of ICIs is supported by the award of the Nobel Prize in Medicine in 2018 to the two immunologists who were at the origin of the concept of ICI-based immunotherapy, James Allison and Tasuku Honjo.³
 
Perhaps the most revolutionary effect of ICI therapy was in the possibility of long-term remission. ICIs have improved treatment outcomes, and durable response has been seen even after stopping treatment.⁴ For some cancer types, such as melanoma, about 20% of patients achieve a complete response (CR), meaning the disappearance of all visible metastases. For many of these CR patients it is now possible to stop treatment after 6 months because the risk of relapse is less than 10% over a five-year follow-up period. Unfortunately, while about 20% of melanoma patients see CR, not all cancer types respond as well as melanoma to ICIs.⁵ In general, ICIs efficacy is specific to a small number of patients.⁶

CHALLENGES IN ICI THERAPY

While ICI treatment is a promising strategy that often offers positive therapeutic outcomes, tumor innate or acquired resistance to ICIs along with associated toxicities lessen their clinical utility. Overall, about 30-40% of patients (for example, in melanoma and lung cancer) who are treated with ICIs show response to intervention.⁷

Tumor Inherent or Acquired Resistance to ICIs

The resistance to ICIs appears to be primarily caused by alterations in the tumor microenvironment (TME). The TME consists of the normal cells, molecules, and blood vessels that surround and feed a tumor cell. A tumor can change its microenvironment, and the microenvironment can affect how a tumor grows and spreads.⁸ The TME maintains angiogenesis (blood vessel formation) and blocks immune cell antitumor activities, facilitating tumor cells’ evasion from host immunosurveillance⁹ (the processes by which cells of the immune system look for and recognize foreign pathogens such as cancer cells).
 
It is now generally understood that tumor cells closely interact with the cells in the TME that support chronic inflammation, increasing modification of the immune response and promoting angiogenesis, thus supporting tumor cells’ escape from recognition and removal by the immune system. Furthermore, developing tumors interact with the TME to prevent T cells from destroying cancer cells through a number of complex processes. Since much ICI treatment is predicated on activating T cells, immune escape may bring about failures in ICI therapy.¹⁰

Treatment-Related Toxicities

Besides resistance, another significant challenge with ICI therapy is treatment-related toxicities. Because ICI mechanisms depend on restraining the physiological brake of immune activation, they may have off-target effects such as immune-mediated inflammation of various organs or tissues. A wide array of immune-related adverse events (irAEs) that resemble autoimmune diseases such as autoimmune thyroiditis have been reported, and can even lead to permanent conditions such as hypothyroidism or irritable bowel syndrome. ICI-related deaths are rare, but they may occur with severe events such as myocarditis or encephalitis.¹¹

Not surprisingly, stopping immune checkpoint signaling can have many negative consequences. Treatment with CTLA4 inhibitors can result in a high incidence of dose-dependent toxicities (high-grade toxicities in 38.6% and 57.9% of patients with metastatic melanoma receiving ipilimumab 3 mg/kg or 10 mg/kg, respectively). By contrast, PD1 or PDL1 blockade causes high-grade adverse events in only 10-15% of patients, with similar incidences seen with different agents and across the range of clinically used doses.¹²

NEW DEVELOPMENTS IN ICIs

To enhance and increase the ORR and durable response rate with ICI treatment, many combination strategies and new targets for immunotherapy drugs are under development. Another area of future research is in identifying biomarkers that could help select patients who would benefit from ICI treatment the most while avoiding significant toxicities.
 

Combination Therapies

To improve response to therapy, combination strategies have been used. For example, anti-CTLA4 agents have been used in conjunction with anti-PD1/PDL1 treatments. Although improved responses have been seen, the incidence and severity of toxicities is a concern.¹³ Combination therapy with ICIs and other therapeutics are under study for a vast array of treatments including chemotherapy, radiotherapy, HER2-targeted therapies, anti-angiogenic agents (anti-VEGF), cancer vaccines, and CAR-T therapies. Early results indicate that combination treatments can address tumor resistance to immune checkpoint blocked therapy. However, the associated irAEs remain an issue for combination treatments.¹⁴
 
Combination therapy with CAR-T cells and ICIs may be a particularly promising strategy. As discussed previously, immune checkpoint pathways such as PD1, PDL1, or CTLA4 in the TME can lower antitumor immunity. One of the primary sources of no response or a weak response to CAR-T cell therapy is poor T cell expansion and short-term T cell persistence. It has been posited that development of this T cell exhaustion is triggered by co-inhibitory pathways. Thus, combination therapy with CAR-T cells and checkpoint blockade could be the next immunotherapy frontier as it provides the two elements necessary for strong immune responses: CAR-T cells, which provide the infiltrate to the tumor and PD1/PDL1 blockade, which can ensure sustained T cell persistence and function.¹⁵
 
Another potentially promising combination strategy pairs ICIs with HDAC inhibitors. Epigenetic regulations can be changed in oncogenesis, favoring tumor progression. The development of epidrugs like HDAC inhibitors has permitted the successful targeting of these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently demonstrated that epigenetic alterations can also play an important role in tumor immune escape. Epidrugs such as HDAC inhibitors can prime the anti-tumor immune response, thus becoming interesting potential partners to develop combination strategies with immunotherapy agents.¹⁶
 

New Targets and Biomarkers

In addition to combination strategies, there are numerous investigational molecules in Phase I and Phase II trials being developed for new inhibitory immune checkpoint targets such as LAG-3, TIM-3, the B7 family, and many more. Many inhibitory targets beyond immune checkpoints are under study as well. For example, interleukins (IL-1, IL-1R3, IL-8) regulate inflammation and innate or acquired immunity, but IL-1 overexpression in malignant cells contributes to chronic inflammation within the TME and T cell exhaustion making them an attractive target. Another possible new target, the angiopoietin ANG-2, disrupts vascular integrity, contributes to inflammation, and is overexpressed in the TME.¹⁷ As mentioned previously, there were over 3,000 active trials of ICI therapies in 2020, and the number has no doubt continued to grow since then.
 
Another important area of research with ICIs is determining predictive biomarkers to identify which patients will benefit the most from ICI treatment while avoiding significant toxicities. Currently approved biomarkers include tumor PDL1 expression by immunohistochemistry, microsatellite instability, and tumor mutational burden. New tumor and immune tissue biomarkers under study include tumor, stromal, and immune cell gene expression profiling and liquid biomarkers such as systemic inflammatory markers, circulating immune cells, cytokines, and DNA. Future development may make it possible to select treatments according to the patient’s individual immune system, including early modification of treatment based on rise or fall of cytokines, circulating immune cell populations and circulating tumor DNA.¹⁸

CONCLUSION

In summary, ICIs were a revolutionary development in cancer treatment when the first CTLA4 inhibitor was approved by the FDA in 2011. New developments in the field continue to offer hope of greater response and less toxicity for cancer patients.