ACTG Blog
Cancer immunotherapy has been hailed as the most promising treatment against cancer in recent decades, but what exactly is immunotherapy? Would immunotherapy be suitable for me?
Immunotherapy is a type of cancer treatment that provokes the patient’s own immune system to fight the cancer. Currently, two categories of immunotherapy have been approved by the USFDA:
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• Immune Checkpoint Therapy—The first checkpoint inhibitor – Ipilimumab (Yervoy) – was approved by the USFDA in 2011 and there are currently six approved checkpoint inhibitors for the treatment of a variety of cancer types.
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• CAR T-Cell Therapy—In 2017, two types of CAR-T cell therapies – Kymria™ (tisagenlecleucel) and Yescarta™ (axicabtagene ciloleucel) – were approved by the USFDA to treat blood cancers.
Many other types of cancer immunotherapy are being researched and developed such as cytokine therapy, oncolytic virus therapy and cancer vaccine, but they are still to be approved by the USFDA.
How Does Immunotherapy Work?
Immune Checkpoint Therapy
Taking the Brakes off the Immune System
A key feature of the immune system lies in its ability to distinguish between healthy cells (self) from abnormal cells (non-self) before attacking the abnormal cells. To avoid accidentally damaging healthy cells, the immune system has a "checkpoint" system, where normal cells can activate the "brake" on T cells to stop an immune attack.
Cancer cells evolve from normal cells, and cancer cells often have mutated proteins present on their cell surface that allows immune cells to flag them as being foreign. However, cancer cells can evade immune attack by mimicking normal cells to activate a "STOP" button on the T cells, which acts in the same way as the "brake" activated by normal cells, to prevent the immune cells from attacking cancer cells.
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Immune checkpoint therapy involves the use of an immune checkpoint inhibitor. An immune checkpoint inhibitor works by turning off the checkpoint mechanism, which prevents the cancer cell from activating the stop on T cells. The T cells become activated again and can attack the cancer cells.
Immune checkpoint inhibitors have been approved for various types of solid tumors including lung cancer, stomach cancer, liver cancer, colorectal cancer, head and neck cancer, kidney cancer, and others. Currently, several clinical trials are also evaluating the role of immune checkpoint inhibitors in combination with chemotherapy or targeted therapy.
Side Effects
Checkpoint inhibitors may cause T cells to become overactive. Some common side-effects include skin rash and flu-like symptoms. Serious side-effects can occur but only in a very small percentage of patients.
Checkpoint Inhibitors currently approved by the USFDA (as of 2020/02):
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• Pembrolizumab (Keytruda®)
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• Nivolumab (Opdivo®)
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• Atezolizumab (Tecentriq®)
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• Ipilimumab (Yervoy®)
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• Avelumab (Bavencio®)
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• Durvalumab (Imfinzi®)
Merck's Keytruda grasps FDA approval again with TMB-H biomarker regardless of tumor type (2020/07/07)
http://www.actgenomics.com/en/clinical_news/keytruda-tmb
CAR T-Cell Therapy
A "Living Drug"—Genetically Modifying T Cells to Fight Cancer
In CAR T-Cell therapy, a patient's own T cells are first extracted from blood, and then genetically modified to add special receptors to their surface. The added receptors are called Chimeric Antigen Receptors (CARs) and they help the T cells recognize and attack cancer cells. Next, the modified T cells are multiplied and returned into the patient’s body. CAR T-cell therapy is a one-time treatment.
The main side effects of CAR T-cell therapy include high fevers, body aches, fatigue, and nausea. A small number of patients have developed more serious side-effects such as low blood pressure and swelling in the brain that can potentially be fatal. CAR T-cell therapy has shown remarkable responses in several kinds of blood cancers, but the clinical results in solid tumor have been much less encouraging. CA T-cell therapy is still a very new form of cancer treatment, and researchers are working hard to make it safer and effective for more types of cancers.
Would Immunotherapy Be Right for Me?
Immunotherapy has shown impressive and durable outcomes for some patients who have failed with multiple other lines of treatment. Immunotherapy, however, is certainly no miracle cure just yet. In addition to the astronomical price and the risk of side effects, the biggest problem faced with immunotherapy is its low response rate, with only approximately 20% of patients responding to treatment on average.
So are there ways to tell if a patient might benefit from immunotherapy? Physicians can now predict whether checkpoint inhibitors will work on someone by using "biomarkers." Biomarkers are biological characteristics at the DNA or protein level that can help doctors detect the presence of a disease or predict a response to treatments.
For immune checkpoint inhibitors, the main predictive biomarkers are as below.
Genomic Biomarkers
• Microsatellite Instability, MSI—Microsatellite instability is a form of genetic instability that results from defects in the DNA’s repair system. MSI-high patients have a higher chance of response to immunotherapy.
• Tumor Mutational Burden, TMB—TMB is the total number of mutations harbored by the tumor. High TMB is associated with a higher chance of response to checkpoint inhibitors.
• Immune-related Genes—When mutations are found in immune-related genes, there will be a higher chance of resistance to immunotherapy.
Non-genomic Biomarkers
• PD-L1 Expression—PD-L1 is a protein which can stop T cells from killing cancer cells. A high PD-L1 level is associated with a higher chance of response.
• Tumor-infiltrating Lymphocytes, TILs—A TIL is a type of immune cell that has moved into a tumor cell, and is associated with a higher chance of response.
• Immunosuppressive Cytokine—A higher number of immune-suppressing cytokines (a type of signaling molecule) is associated with a lower chance of response.
Using biomarkers to identify suitable patients is becoming a standard for immunotherapy
In May 2017, checkpoint inhibitor Pembrolizumab (Keytruda) was approved by the USFDA for all solid tumors with high microsatellite instability (MSI-high). Previously, the USFDA was approving cancer drugs based on the original location of the tumor (for example, approving a drug for lung cancer). Pembrolizumab is the first cancer drug that was approved based on the presence of a tumor biomarker or a specific genetic feature, rather than the type of cancer.
Using multiple biomarkers can increase the prediction accuracy
Currently, PD-L1 is the biomarker most commonly used by doctors to predict the immunotherapy response, but selecting patients solely based on the PD-L1 test results may be insufficient. A 2017 study showed that the response rate of patients who were both TMB-high and PD-L1-high was approximately twice as high as patients who were only TMB-high or only PD-L1-high (David P. Carbone et al.N Engl J Med. 2017;376:2415-26).
PD-L1 testing can usually be ordered from your hospital or facility. The three main genomic biomarkers for checkpoint inhibitors – MSI, TMB, and immune-related genes – can be evaluated using ACTOnco®+ comprehensive genomic profiling. With the high price tag and the risk of side effects associated with immunotherapy, it is essential to identify only the patients who are most likely to benefit.