Immune Checkpoint Inhibitors in Cancer Treatment
By Alexander An on September 25th, 2023
Every major pharmaceutical and biotechnology company hopes to create the next blockbuster drug that will benefit all patients. An example of this is the immunotherapy Keytruda (pembrolizumab). Keytruda, a humanized PD-1 inhibitor monoclonal antibody, generated a staggering $21 billion in sales in 2022 alone. This drug belongs to the drug class called immune checkpoint inhibitors.
Checkpoint proteins like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte-activation gene 3 inhibitors (LAG-3), programmed cell death protein-1 (PD-1), and its ligand-1 (PD-L1) have been the subject of much investigation. The Nobel Prize was awarded to James Allison and Tasuku Honjo in 2018 for "discovering cancer therapy by inhibiting negative immune regulation." They demonstrated strategies for blocking the immune system's brakes, which can be utilized to treat cancer. In addition, compared to conventional treatments like chemotherapy, adverse effects have been reduced by targeting specific immune system proteins.
Figure from https://doi.org/10.3390/clinpract13010003
So, how do immune checkpoint inhibitors like pembrolizumab or ipilimumab work?
Immune checkpoints are proteins found on the surface receptors of immune cells, responsible for regulating the immune system. However, cancer cells occasionally manage to evade these checkpoints to protect themselves from immune system attacks. This is where immune checkpoint inhibitors (ICIs) come in. ICIs help restore the function of the immune system by blocking immune cell receptors such as CTLA-4 on T lymphocytes. ICIs are also sometimes used in combination with surgery, chemotherapy, or radiation therapy to enhance the effectiveness of antitumor effects.
Table from https://doi.org/10.1186/s13045-021-01056-8
CTLA-4, an immunoglobulin superfamily coinhibitory member, interacts with its ligands B7-1 (CD80) and B7-2 (CD86) to negatively limit the activation of T lymphocytes. Early research by James Allison showed that inhibiting CTLA-4 in mice could prevent the growth and development of tumors. Additionally, it assisted mice in developing immunological memory and repeatedly rejecting tumor development. The drug enables T-cells to activate and destroy cancer cells by inhibiting CTLA-4. Consequently, humanized monoclonal antibodies that prevent CTLA-4 from binding with the B7 ligands were created and proved successful in clinical studies. Bristol Myers Squibb (BMS) developed the first CTLA-4 monoclonal antibody inhibitor, ipilimumab, which was approved in 2010 for the treatment of melanoma. Over a period of 2.5 years, the treatment has increased survival rates and maintained a sustained response.
Yasuku Honjo identified the binding of PD-1/PD-L1-induced T-cell exhaustion. In preclinical models, PD-L1 inhibition is blocked, and T-cell activation is increased. In the tumor microenvironment, various immune cell types have been found to express PD-1, a member of the immunoglobulin superfamily, more than CTLA-4. In contrast to CTLA-4, PD-1 restricts T-cell activation in peripheral tissues during the later stages of tumor development. A PD-1 inhibitor called pembrolizumab, created by Merck, has proven effective for numerous cancer indications, including melanoma, NSCLC, cervical cancer, and more. Nivolumab, a drug developed by BMS in 2014 for melanoma, is the second PD-1 inhibitor. Cemiplimab, a humanized IgG4 antibody created by Regeneron Pharmaceuticals and Sanofi Genzyme, was the most recent PD-1 inhibitor to receive FDA approval for treating cutaneous squamous cell carcinoma. Overall, it has been demonstrated that cemiplimab outperforms EGFR inhibitors and chemotherapy in terms of overall survival and progression-free survival.
PD-1 employs PD-L1 and PD-L2 to block activated immune cells. In contrast to PD-L2, which is primarily found in dendritic cells, PD-L1 is expressed in various tumor types. Atezolizumab, durvalumab, and avelumab are the three PD-L1 inhibitors with FDA approval currently available. The humanized IgG1 monoclonal antibody atezolizumab, developed by Genentech, was initially authorized in 2016 to treat urothelial cancer. Its indications have been extended to include NSCLC, SCLC, melanoma, and hepatocellular carcinoma due to the successful response rates.
LAG-3, a co-inhibitory protein and a member of the Ig superfamily, is found in regulatory T cells with immunosuppressive properties and cytotoxic CD8 T cells. When combined with PD-1 inhibition, reducing LAG-3 enhances CD8 T cell responsiveness both directly and indirectly by decreasing regulatory T cell mechanisms, leading to additive anticancer effects. The most recent class of ICIs to receive FDA approval in the United States is LAG-3 inhibitors. Relatlimab, the only LAG-3 inhibitor currently used in clinical trials, is available only in a fixed-dose combination with nivolumab for the treatment of metastatic melanoma.
Table of FDA-approved predictive biomarkers from https://doi.org/10.1038/s41392-023-01522-4
A deeper understanding of predictive biomarkers is required to identify which patient population will respond well to immunotherapy because not every patient receiving an ICI will. PD-L1 status, microsatellite instability (MSI)/DNA mismatch repair system (dMMR), and tumor mutational burden (TMB) are the biomarkers that have received FDA approval. Immunohistochemical staining is used to measure the patient's PD-L1 levels after a solid tumor diagnosis. The FDA granted approval for the PD-L1 test in 2015. It measures the proportion of tumor cells that express PD-L1. For instance, checkpoint inhibitors like pembrolizumab work well against cancers that express PD-L1 at levels of 50% or above.
The second biomarker is the presence of microsatellite instability (MSI), a characteristic of numerous malignancies where there is a replication error in the DNA, such as a mismatch. MSI is the term used to describe the high rate of mutations that alter the length of the microsatellite sequence. As a result, apoptosis may be avoided, and mutations may accumulate, leading to tumorigenesis and the generation of neoantigens.
TMB, or the quantity of mutations per megabase in cancer cells, is the last biomarker predictor approved by the FDA. Both blood and solid cancers have been treated with this biomarker. The threshold for elevated TMB varies by tumor type, and combining biomarkers helps determine how well patients may respond to immunotherapy. Patients with higher TMB respond better to anti-PD-L1 and anti-CTLA-4 in NSCLC, melanoma, and bladder cancer.
The treatment of cancer has evolved substantially during the past years thanks to immune checkpoint inhibitors. However, both intrinsic and extrinsic resistance can cause some individuals to become resistant to ICIs. PD-L1 downregulation, immunosuppression, phenotypic alterations of tumor cells, and other factors contribute to intrinsic resistance. By upregulating inhibitory immunological checkpoints such as PD-1, CTLA-4, and LAG-3, cancer cells can also bypass the immune system, reducing the effectiveness of ICIs. But no worries. Bispecific antibodies and antibody-drug conjugates are two examples of how the science of immunotherapy is heading toward a combination approach. We anticipate better patient outcomes in the future with that combo strategy.
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