Aaron Logsdon
Abbreviations
CAR, chimeric antigen receptor; CAR-T, chimeric antigen receptor T lymphocyte therapy; CRC, colorectal cancer; DCR, disease control rate; dMMR, mismatch repair-deficient; FDA, US Food and Drug Administration; ICI, immune checkpoint inhibition; MMR, mismatch repair genes; MSI-H, high microsatellite instability; MSS, microsatellite stable; OR, objective response; pMMR, mismatch repair proficient; Treg, T regulatory lymphocytes
Glossary
antigen, anti-tumour immunity, benign, blood vessel, bone marrow, cancer vaccine, cell, cell proliferation, chemotherapy, chimeric antigen receptor, clinical trial, colon, colorectal cancer, cytokine, cytotoxic T lymphocyte, dendritic cell, diagnosis, DNA, efficacy, enzyme, microbiome, helper T lymphocyte, microsatellite instability, immune cell, immune checkpoint inhibitor, immune response, immune system, immunotherapy, irradiation, lymphatic vessel, metastasis, microsatellite, monoclonal antibody, mucosa, mutation, neoantigen, nucleotide, objective response, polyp, prognosis, radiotherapy, receptor, rectum, regulatory T lymphocyte, sporadic cancer, stem cell, synergistic, tissue, tumor, tumor microenvironment, US Food and Drug Administration
Colorectal cancer and how it is treated
How colorectal cancer develops
Colorectal cancer (CRC) originates in the walls of blood vessels in either the colon or rectum (Haraldsdottir et al., 2014). Most CRCs begin as growths called polyps, within the inner lining of the colon or rectum. The type, size, and the number of polyps determine whether or not these growths develop into cancer. The polyps that develop into cancer can grow into the wall of the colon or rectum, which is made up of four distinct layers of different types of cells.
CRC begins in the innermost layer of the colon/rectum wall, the mucosa, and progressively grows outward into the outer layers forming a tumor (Figure 1). The CRC cells can subsequently invade blood vessels and lymphatic vessels, which carry away tissue waste and fluid. In this way, the tumor cells can spread to distant body parts where they can form secondary tumors (Simon, 2016). This process is known as metastasis.
Figure 1. The development of CRC in the colon/rectal wall (created using BioRender.com)
Traditional CRC treatment
It is estimated that approximately 935,000 CRC-related deaths occurred in 2020 worldwide, accounting for one in ten of all cancer-related deaths (Sung et al., 2021). However, advanced CRC patients (those whose cancer in the colon/rectum is at an advanced stage or has spread to other body parts) rarely survive for more than two years following their diagnosis (Pericay et al., 2018). Primary treatments for CRC consist of surgery, chemotherapy, and radiotherapy. Surgery is unlikely to be effective in advanced CRC patients, whilst chemotherapy and radiotherapy can cause significant damage to the body as they can destroy normal cells as well as cancer cells.
Chemotherapeutic drugs are normally administered into the bloodstream where they target rapidly growing cells. Cancer cells are known to replicate more rapidly than normal cells. However, normal cells also grow and replicate, and therefore, some normal cells are also targeted by these drugs. This results in the killing of some normal cells and this can lead to unpleasant side effects as well as harmful complications such as injury to heart muscle (Von Hoff et al., 1979). With radiotherapy, which is another type of treatment that is used to destroy cancerous cells, high-energy radiation is used to target tumors. Radiotherapy can also cause damage to normal cells that are in close proximity to the site of the tumor. This can also lead to unpleasant side effects as well as injury to healthy tissues of the body. For example, radiotherapy given for colorectal cancer can cause gastrointestinal radiation injury, which in turn reduces the patient’s quality of life (Bacon et al., 2001; Bacon et al., 2002).
In summary, doctors currently face several problems and difficulties when it comes to the current primary treatments available for the treatment of advanced CRC as these often fail to give advanced CRC patients a good prognosis and can also lower a patient’s quality of life. Therefore, it is necessary to develop novel therapeutic approaches such as immunotherapies that can treat CRC more efficiently and effectively and with greater precision.
Immunotherapy as a treatment for CRC
The immune system is our first line of defence against cancer. Immune cells patrol the body, on the lookout for abnormal cells such as cancer cells. The immune cells target and destroy cancer cells via specific interactions. However, cancer cells have developed numerous mechanisms for bypassing the immune system by impeding the immune system to prevent an immune response or by evading detection by masking themselves as normal cells.
Immunotherapy makes use of our knowledge of immune processes that naturally occur in our body and manipulates the specific, complex interactions between cancer cells and our immune cells to boost the functioning of the immune system. This allows the immune system to target and kill the cancer cells more precisely and effectively, with fewer side effects than are experienced with chemotherapy or radiotherapy.
Figure 2. The advantages of treating cancer with immunotherapy over traditional treatments. Immunomemory refers to the immune system’s ability to recognize previous threats to the body, such as the same type of infection or cancer, and to respond more quickly, effectively, and efficiently when it encounters the same infection or antigen.
Key players of the tumor microenvironment
The tumor microenvironment
To understand the role of the immune system in CRC and how immunotherapy treats CRC, it is necessary to understand the roles of some of the key types of immune cells found in the CRC tumor microenvironment. A tumour microenvironment consists of normal cells (including cells that make up our tissues and organs as well as immune cells) and blood vessels that surround and feed cancer cells. A tumor can alter the components of the microenvironment and the microenvironment can, in turn, affect how the tumor grows and spreads (Whiteside, 2008).
T lymphocytes
One of the most important types of immune cells that are present in the tumor microenvironment is T lymphocytes. T lymphocytes are a type of white blood cell that develop from stem cells that are produced in the bone marrow. Different types of T lymphocytes have different cell surface markers such as CD4 and CD8. CD8+ T lymphocytes have CD8 surface markers. They are cytotoxic T lymphocytes, which means that they kill any foreign and abnormal cells that they interact with. Cytotoxic T lymphocytes are the main effectors (killers) of antitumor functioning (Figure 3) (Kather et al., 2018).
Another type of T lymphocyte is the CD4+ T lymphocyte, which is also known as a helper T cell or helper T lymphocyte. Helper T lymphocytes help to both regulate the activity of cytotoxic T lymphocytes, and to determine the immune response to tumors and foreign cells, such as bacterial cells (Figure 3). A further type of T lymphocyte is the regulatory T lymphocyte (Treg). Tregs suppress the action of cytotoxic and helper T lymphocytes, thereby essentially ´switching off ´ an immune response, for example when a tumor has been eradicated and action of the cytotoxic and helper T cells is no longer required (Figure 3) (Kather et al., 2018).
Figure 3. The modes of action of the different types of T lymphocytes. Cytokines are messengers of the immune system, while dendritic cells present molecules, such as antigens that are present on the surface of cancer cells, to T lymphocytes to activate the T lymphocytes to mount an immune response to eliminate the cancer cells.
The role of the immune system in CRC immunotherapy
The concept of immunotherapy in CRC
The use of immunotherapy in CRC is based on the concept that Treg-derived suppression of immune system activity is one of the main mechanisms of evasion that is employed by cancer cells. Tumour cells can manipulate cytokine (messengers of the immune system) production thereby inducing Treg-derived suppression of cytotoxic T lymphocyte function. This has the effect of reducing the activity of both CD4+ and CD8+ T lymphocytes, which subsequently lose their ability to recognize foreign surface markers on the surface of cancer cells. This thereby allows the cancer cells to evade detection by the immune system and to continue to persist and proliferate (Golshani & Zhang, 2020).
Immune checkpoint molecules
Tumor cells can also upregulate the expression of immune checkpoint molecules such as PD-L1, which can exhaust the activity of T lymphocytes in the tumor microenvironment and can also inhibit the killing of cancer cells (Golshani & Zhang, 2020). Immune checkpoint molecules are key modulators of the anti-tumor T lymphocyte immune response and are expressed on the surface of both T lymphocytes and cancer cells.
When T lymphocytes and cancer cells interact via immune checkpoint molecules, this interaction can either activate or inhibit T lymphocyte anti-tumor activity. When the PD-L1 molecule present on the surface of cancer cells engages the PD-1 molecule present on the surface of T lymphocytes, this interaction leads to the inhibition of T lymphocyte anti-tumor activity (Tumeh et al., 2014). This inhibition cancels out the T lymphocyte activating effect of MHC molecules on the cancer cell surface interacting with TCR molecules on the surface of T lymphocytes. MHC is a presenting molecule and TCR is a T lymphocyte surface molecule that can recognize MHC molecules. MHC can present the unique surface markers of the cancer cell to the TCR, resulting in activation of the T lymphocyte, which then targets and destroys the cancer cell.
Mismatch repair genes and microsatellite DNA
When cells divide, the DNA contained within them is replicated. This results in two daughter cells (products of the parent cell dividing into two). Each new daughter cell has a complete set of DNA, identical to the parent cell. Mistakes can occur during the process of cell division, resulting in mutations that can occur at singular or multiple positions within the DNA sequence. Mutations can result from the insertion or deletion, or duplication, or translocation of particular nucleotides. It is the role of mismatch repair (MRR) genes to correct these mistakes. In approximately 15% of sporadic colon cancer cases (cases that are not linked to any family history of CRC disease), the MMR genes are deficient (dMMR) and fail to correct these mistakes (Le et al., 2015). dMMR CRC tumours are described as microsatellite instability-high (MSI-H) as they fail to correct mistakes made within repetitive regions of the DNA that are called microsatellites. dMMR/MSI-H CRC tumours tend to have a high mutational burden, meaning that they carry many of these types of mistakes in the DNA of their cells (Figure 4). The high mutational burden results in the expression of numerous, unique markers on the surface of cancer cells, which are recognized as being foreign by our immune system, thereby making the cancer cells easier to detect and destroy (Golshani & Zhang, 2020). This is why dMMR/MSI-H CRC tumors have relatively favourable prognoses in comparison to CRC tumors that express proficient MMR (pMMR) genes and stable microsatellite (MSS) DNA. pMMR/MSS tumors have low mutational burdens and express fewer cell surface markers that can be detected by the immune system (Figure 4). However, only 3-6% of advanced CRC patients have dMMR/MSI-H tumors, with the majority of CRC patients having pMMR/MSS type tumors. (Nosho et al., 2010).
Figure 4. How a pMMR complex handles a replication error compared to a dMMR complex. DNA is composed of the nucleotides adenine, thymine, cytosine, and guanine, which are normally represented by the letters A, T, C, and G. The specific sequence of these bases encodes all of our genes, with each gene coding for a specific protein. DNA is a double-stranded molecule in which the A on one strand pairs with a T on the other, while the C nucleotides on one strand pair with G nucleotides on the other strand. Here, A has been incorrectly paired with a C due to a replication error within microsatellite DNA. This error must be corrected to prevent instability in that area of the DNA. The enzymes encoded by dMMR genes are unable to correct this error and only functional enzymes encoded by pMMR genes can successfully make these corrections.
Tumors that are MSI-H have an upregulated expression of immune checkpoint molecules such as PD-L1. This helps cancer cells to evade detection by the immune system (Llosa et al., 2015). MSI-H acts as a predictive marker for a positive response to PD-L1 targeted therapy, with a subset of advanced CRC patients with dMMR/MSI-H tumours showing profoundly positive responses to this type of therapy (Golshani & Zhang, 2020).
Use of immunotherapy to treat dMMR/MSI-H advanced CRC
Immune checkpoint inhibitors
Immune checkpoint inhibitors can prevent immune checkpoint molecules from interacting with each other, effectively turning off their effects. Currently, two immune checkpoint inhibitors that target PD-1 have been approved for use (only for dMMR/MSI-H CRC patients) by the United States Food and Drug Administration (FDA), and these are the drugs pembrolizumab by Merck & Co, and nivolumab by Ono Pharmaceutical (Golshani & Zhang, 2020). Both of these drugs are examples of monoclonal antibodies, which are antibodies that are produced from identical B lymphocytes, all of which produce the same antibody. This type of therapy is referred to as immune checkpoint inhibition (ICI), as it prevents the PD-L1 present on the surface of the cancer cell from interacting with the PD-1 molecule on the surface of the T lymphocyte, thereby preventing T lymphocyte inhibition (Figure 5). This then, allows the cancer cell to be recognized by the immune system.
Figure 5. How ICI blocks T lymphocyte inhibition. PD-1 can interact with PD-L1 to turn the previous interaction off. However, the monoclonal antibodies (the three armed red objects) can inhibit the PD-1/PD-L1 interaction, meaning the T lymphocyte stays activated against the cancer cell (created using BioRender.com).
Clinical trials
Clinical trials are large scale experiments that help determine whether a new drug can treat target patients with greater efficacy and less toxicity than the current gold standard used to treat said target patients. If the new drug is successful, it will be approved for use in the target patients. The phase of a trial represents the stage of testing a new treatment is at. If a treatment passes one phase, it can move on to the next. There are generally three phases, phase I-III. If clinical trials are successful, the drugs being trialled gets approved by governing bodies (in the USA, the FDA) for use in the clinic. Success can be measured by a number of things e.g., objective response (OR) of patients on trial and disease control rate (DCR) of patients on trial. The OR simply means “a measurable response” and DCR is a measure of how long an individual’s disease is kept from progressing to a more severe stage.
A clinical trial that began in February 2014 called KEYNOTE 028 studied the effects of pembrolizumab treatment in advanced CRC patients with dMMR/MSI-H tumours as well as in advanced CRC patients with pMMR/MSS tumours (Le et al., 2015). All of the patients included in the trials had failed to respond to first-line treatment with chemotherapy. First-line therapy is the standard and first treatment type that is offered to a patient. In the case of CRC, the first-line treatment given, is usually surgery, chemotherapy, or radiotherapy.
A 40% OR was observed in the dMMR/MSI-H patients compared to 0% OR observed in the pMMR/MSS patients. A DCR > 12 weeks was seen in 90% of the dMMR/MSI-H patients but was only 11% in the pMMR/MSS patients (Le et al., 2015). Therefore, the results of the trial demonstrated that there is a clear benefit to giving pembrolizumab treatment to advanced CRC patients with dMMR/MSI-H tumours who have not responded to chemotherapy. Pembrolizumab was approved for the treatment of advanced CRC patients with dMMR/MSI-H tumors by the FDA in May, 2017 (Table 1).
Another clinical trial that began in March 2014, called CheckMate 142, studied the effects of nivolumab treatment as well as of nivolumab in combination with another monoclonal antibody, ipilimumab in advanced CRC patients with dMMR/MSI-H tumors as well as in advanced CRC patients with pMMR/MSS tumors (André. et al., 2018; Le et al., 2017). None of the patients that participated in the trial responded to first-line chemotherapy. The results the trial showed that only the dMMR/MSI-H patients appeared to benefit from nivolumab treatment, with 68% DCR > 12 weeks, increasing to > 80% when the ipilimumab was administered in combination with nivolumab. The two trials demonstrated that the administration of nivolumab treatment to advanced CRC patients with dMMR/MSI-H tumours that had not responded well to chemotherapy, provides a clear benefit. Nivolumab was approved for the treatment of advanced CRC patients with dMMR/MSI-H tumours by the FDA in August, 2017 (Table 1) (André. et al., 2018; Le et al., 2017).
Table 1. Landmark ICI trials investigating the clinical use of pembrolizumab and nivolumab in CRC treatment. OR and DCR columns refer to dMMR/MSI-H CRC patients in the studies
Use of immunotherapy to treat patients with pMMR/MSS advanced CRC
The problem with pMMR/MSS CRC tumours and potential solutions
As the results of the clinical trials mentioned demonstrate, ICI is designed for dMMR/MSI-H CRC patients, meaning that it only shows a benefit in approximately 4% of advanced CRC cases (Gryfe et al., 2000; Kawakami, Zaanan & Sinicrope, 2015). Around 80% of CRC cases are pMMR/MSS patients, meaning that giving ICI treatment alone does not improve the disease prognosis in the majority of CRC patients (Golshani & Zhang, 2020).
The KEYNOTE 028 and CheckMate 142 ICI trials demonstrated that the DCRs and ORs of pMMR/MSS patients was significantly lower than that of dMMR/MSI-H patients. As previously stated, the pMMR genes and resulting stable microsatellite DNA result in a tumor having a relatively low mutational burden. This together with immune checkpoint molecules such as PD-L1 not being significantly upregulated, leads to the lack of response to ICI in pMMR/MSS CRC patients. Therefore, pMMR/MSS CRC is thought to be an “immunologically cold” tumor class, meaning that these patients usually do not respond to current immunotherapy treatment. However, it is believed that incorporating ICI in a combination therapy could create an “immunologically warmer” tumor class that may increase the effectiveness of ICI in these patients (Arora & Mahalingam, 2018). The combination theory was seen as a possibility when chemotherapy and radiotherapy caused cancer cells to die and release damage-associated molecular patterns, which are danger signals sent by our cells to notify the immune system of an infection or in this case, cancer. Dendritic cells can present these patterns to cytotoxic T lymphocytes, activating the latter against the cancer cells (Overman, Ernstoff & Morse, 2018; Krysko et al., 2012; Bracci et al., 2014; Apetoh et al., 2007). Potential partner treatments that could be combined with ICI include MEK inhibition and CRC vaccines.
Potential role of MEK inhibition
MEK is a molecule that helps to convey specific signals from outside the cell, into the nucleus of the cell. These signals cause the cell to divide. MEK is a part of a pathway called the MAPK pathway (Figure 6) (Ciardiello et al., 2019).
Figure 6. The MAPK pathway. A signal that arrives from the outside the cell interacts with a cell surface molecule called a receptor. The receptor becomes activated, leading to a series of molecules including MEK being activated. These activations eventually lead to alterations in the DNA, causing the cell to divide. Inhibiting one component of this pathway, such as MEK, disrupts the pathway, preventing the signal from being transmitted effectively.
Experiments performed using preclinical models of disease such as mouse models, have been used to demonstrate that inhibiting MEK can lead to an upregulation in the expression of MHC molecules on the surface of tumor cells (Ciardiello et al., 2019). This increases the number of cytotoxic T lymphocytes that migrate into the tumor microenvironment. This is due to the MHC molecule’s ability to present unique cancer surface markers to T lymphocytes and to activate them against cancer cells. This could potentially transform an immunologically cold tumor such as a pMMR/MSS CRC tumour, into one that can be effectively treated with ICI. This potential was partly realized when mouse models showed that a combination treatment of PD-1 inhibition and MEK inhibition was more effective in inhibiting tumor growth in mice when compared to the results of ICI treatment alone, indicating a potential synergistic effect of the combination (Liu et al., 2015; Ebert et al., 2016). However, a phase III clinical trial (ClinicalTrials.gov identifier: NCT02788279) demonstrated that the overall survival of advanced CRC patients (patients who did not respond to chemotherapy) only increased by 1.8 months when treated with the MEK/PD-1 combined inhibition, rather than with the PD-1 inhibition alone (Eng et al., 2019). Therefore, it will be necessary to conduct further clinical trials to test further combinations of MEK inhibition and ICI drugs on advanced CRC patients with pMMR/MSS tumors.
Potential role of cancer vaccines
A cancer vaccine is a treatment that induces specific immune responses against the particular markers that are present on the surface of cancer cells (Ciardiello et al., 2019). When present on normal cells, these surface markers are referred to as antigens, but when these antigens are present on the surface of cancer cells, they are referred to as neoantigens. Such neoantigens are unique to the cancer cells and therefore targeting these molecules causes minimal damage to normal cells. A promising class of cancer vaccine is the neoantigen vaccine, which uses neoantigens from the patient’s cancer cells in the composition of the vaccine itself. There is evidence that when the neoantigen vaccine is used, cytotoxic and helper T lymphocytes produce a particular type of cytokine, and that this causes the upregulation of PD-L1 on the surface of cancer cells (figure 7) (Dong et al., 2002; Spranger et al., 2013; Taube et al., 2012; Rekoske et al., 2015; Soares et al., 2015). Inducing the upregulation of PD-L1 in pMMR/MSS CRC would result in the tumor cells in these patients becoming much more susceptible to ICI treatment.
Figure 7. The effects of a neoantigen CRC vaccine. Dendritic cells can present the neoantigen from the vaccine to T lymphocytes, which can then become activated against the neoantigen, which is also uniquely found on the surface of the patient’s CRC cells. Helper T lymphocytes can then interact with CRC cells through the neoantigen to upregulate PD-L1 on the surface of cancer cells. Cytotoxic T lymphocytes can also interact with CRC cells via the neoantigen to kill them.
CRC mouse models have shown this vaccine/ICI combination to be highly effective, resulting in specific immunity being generated against the neoantigens. This immunity results in long-lasting T lymphocyte activity that ultimately leads to eradication of the tumor (Curran et al., 2010; Kuai et al., 2017; Ni et al, 2020; Tondini et al., 2019; Zhu et al., 2017).
However, clinical studies on neoantigen vaccines are still ongoing and it remains to be seen whether a safe and effective neoantigen vaccine could be used in combination with ICI to treat pMMR/MSS CRC patients (Table 2).
Table 2. All known clinical trials currently assessing neoantigen CRC vaccines (https://clinicaltrials.gov/)
The future of immunotherapy in CRC
Introducing immunotherapy at an earlier stage of the disease
Currently, immunotherapy for CRC is only offered as an alternative treatment to patients with advanced CRC who have not responded well to more conventional therapies. However, clinical trials are being conducted to determine whether immunotherapy could potentially be used as a first-line treatment for advanced CRC.
The CheckMate 142 clinical trial assessed the effect of administering a combination therapy of nivolumab and ipilimumab as the first-line therapy in dMMR/MSI-H CRC patients. The overall response rate, which is the proportion of patients who have a partial or complete response to the therapy, was 60%, with 7% of the patients showing no detectable cancer (Lenz et al., 2018). The promising results of this trial, taken together with the fact that immunotherapy inflicts far less physical damage on patients than conventional first-line treatment, means immunotherapy has the potential to become a front line treatment for dMMR/MSI-H CRC patients in future.
The gut microbiome
Microbes are microscopic organisms, such as bacteria and viruses. They are found throughout the body, including in the gut, where there is a diverse community of bacteria and other organisms, which is referred to as the gut microbiome. The number of microbial cells in the body is roughly the same number as the body has your own cells (3.0×1013) (Sender et al., 2016).
Some of the microbes that are present in the gut are beneficial/neutral to the body and are non-pathogenic. These microbes play an important role in digestion and maintaining a healthy balance of microbes in the body, while others can be pathogenic (have the ability to cause disease). However, it is the balance of the different species of commensals that determines the health of the gut microbiome. An unhealthy balance can lead to various diseases, including cancer (figure 8) (Golshani & Zhang, 2020). Currently, it is believed that the composition of the gut microbiome may affect how a patient responds to particular immunotherapy (Hendler & Zhang, 2018).
Several studies have compared the gut microbiomes of patients who have received immunotherapy with those of patients that have not received immunotherapy. The results of these studies demonstrate that patients with epithelial (tissue that lines body surfaces and organs) tumors, that have received PD-L1 and in whom significant alterations in their gut microbiome have not been observed, have far better survival and slower disease progression than those patients whose gut microbiomes have been altered as a result of being given antibiotics (Routy et al., 2018). The precise degree to which the gut microbiome influences a patient’s response to ICI is yet to be determined.
Figure 8. A healthy person’s gut microbiome is often well balanced, while a person with a disease such as cancer can have a very unbalanced gut microbiome, with certain species of commensal bacteria overrepresented, with others being under-represented (created using BioRender.com).
CAR-T therapy
Chimeric antigen receptor T (CAR-T) lymphocyte therapy is another form of immunotherapy. A CRC patient’s T lymphocytes can be collected in a fashion similar to a blood donation. An inactivated virus can then be used to introduce genetic material into the T lymphocyte. The genetic material introduced via the inactivated virus includes the chimeric antigen receptor (CAR), which is a molecule that can interact with molecules on the surface of target cells. In this case, the CAR would have been designed in a laboratory to specifically recognize and interact with some of the surface markers that are present on the CRC cells. The T lymphocyte is now a CAR-T lymphocyte as it can produce CARs on its surface. Millions of the CAR-T lymphocytes expressing the same CAR can be produced in a laboratory and then infused back into the patient. These lymphocytes interact with cancer cells via their CARs and subsequently destroy the cancer cells (figure 9) (Sermer & Brentjens, 2019). CAR-T immunotherapy is currently being investigated for use in CRC in early-stage clinical trials (ClinicalTrials.gov identifier: NCT03152435) (Golshani & Zhang, 2020). While there are still some hurdles to overcome before CAR-T lymphocytes can be used in a clinical setting, CAR-T does have the potential to change the landscape of immunotherapy for CRC.
Figure 9. The basic mechanism of CAR-T therapy (created using BioRender.com).
Conclusion
Immunotherapy is steadily becoming a novel alternative to the more damaging and less specific first-line treatments currently used to treat CRC disease. Immunotherapy for CRC, in the form of ICI, has been successfully used to inhibit the suppression of T lymphocytes, thereby enhancing the ability of the immune system to eliminate cancer cells and improving patient prognosis.
Important landmark clinical trials such as the KEYNOTE 028 and CheckMate 142 trials have demonstrated that current immunotherapy is only effective on a small number of CRC patients who are referred to as dMMR/MSI-H patients. The vast majority of CRC patients, who are pMMR/MSS, generally do not respond well to ICI. This has led to the hypothesis that ICI must first be combined with another treatment to make these patients more responsive to ICI, and immunotherapy as a whole. Avenues such as cancer vaccines and MEK inhibition combined with ICI, have shown some promise, but need to be developed further before the majority of CRC patients can benefit from immunotherapy.
The future for immunotherapy in CRC disease is bright, with many important studies being conducted. A range of treatments ranging from enhancement or rebalancing of the gut microbiome to the use of CAR-T are currently being developed. Ongoing research in this area is leading to new insights that may allow immunotherapy to become the first-line treatment for CRC disease, with the potential of significantly improving patient prognosis and minimizing physical damage to the patient during the treatment process.
Useful links
https://www.cancer.org/cancer/colon-rectal-cancer/about/what-is-colorectal-cancer.html – What is CRC?
https://www.cancerresearchuk.org/about-cancer/bowel-cancer/treatment – First-line treatments for CRC.
https://www.childrenwithcancer.org.uk/childhood-cancer-info/understanding-cancer/treatments/immunotherapy/?gclid=CjwKCAjwy7CKBhBMEiwA0Eb7apfSvjgLBW9wZGYn9XfiPAZTnW_MsQDpl4wb4qi6WApftAfw7QUt9RoCrAUQAvD_BwE -What is immunotherapy?
https://www.webmd.com/cancer/immunotherapy-risks-benefits – Pros and cons of immunotherapy.
https://www.news-medical.net/life-sciences/What-is-the-Tumor-Microenvironment.aspx – The tumour microenvironment.
https://oncologypro.esmo.org/education-library/esmo-handbooks/immuno-oncology/1.1-Immune-Checkpoints – Immune checkpoint molecules.
https://en.wikipedia.org/wiki/Microsatellite_instability – MSI.
https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html – Immune checkpoint inhibitors.
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monoclonal-antibody – Monoclonal antibodies.
https://www.mskcc.org/cancer-care/clinical-trials/what-does-phase-clinical-trial-mean and https://www.youtube.com/watch?v=RuzoAjNyJr0&ab_channel=CLINICALGYAN – Medical trial phases.
https://clinicaltrials.gov/ct2/show/NCT02054806 – KEYNOTE 028.
https://clinicaltrials.gov/ct2/show/NCT02060188 – CheckMate 142.
https://en.wikipedia.org/wiki/Damage-associated_molecular_pattern – Damage
associated molecular patterns.
https://www.youtube.com/watch?v=-dbRterutHY&ab_channel=AmoebaSisters – Explaining cell signalling (helpful for understanding the MAPK pathway).
https://clinicaltrials.gov/ct2/show/NCT02788279 – MEK and ICI inhibition trial.
https://www.youtube.com/watch?v=GB2LOJOl8qA&ab_channel=Genentech – Idea of a neoantigen vaccine.
https://depts.washington.edu/ceeh/downloads/FF_Microbiome.pdf – The gut microbiome.
https://www.youtube.com/watch?v=OadAW99s4Ik&ab_channel=Dana-FarberCancerInstitute – CAR-T therapy.
https://clinicaltrials.gov/ct2/show/NCT03152435 – CAR-T therapy for CRC trial.
References
Apetoh, L., Ghiringhelli, F., Tesniere, A., Obeid, M., Ortiz, C., Criollo, A., Mignot, G., Maiuri, M. C., Ullrich, E., Saulnier, P., Yang, H., Amigorena, S., Ryffel, B., Barrat, F. J., Saftig, P., Levi, F., Lidereau, R., Nogues, C., Mira, J., Chompret, A., Joulin, V., Clavel-Chapelon, F., Bourhis, J., André, F., Delaloge, S., Tursz, T., Kroemer, G. & Zitvogel, L. (2007) Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Medicine. 13 (9), 1050-1059. Available from: doi.org/10.1038/nm1622
Arora, S. P. & Mahalingam, D. (2018) Immunotherapy in colorectal cancer: for the select few or all? Journal of Gastrointestinal Oncology. 9 (1), 170-179. Available from: doi.org/10.21037/jgo.2017.06.10
Bacon, C. G., Giovannucci, E., Testa, M. & Kawachi, I. (2001) The impact of cancer
treatment on quality of life outcomes for patients with localized prostate cancer. The Journal of Urology. 166 (5), 1804-1810. Available from: doi.org/10.1016/S0022-5347(05)65679-0
Bacon, C. G., Giovannucci, E., Testa, M., Glass, T. A. & Kawachi, I. (2002) The association of treatment-related symptoms with quality-of-life outcomes for localized prostate carcinoma patients. Cancer. 94 (3), 862-871. Available from: doi.org/10.1002/cncr.10248
Bracci, L., Schiavoni, G., Sistigu, A. & Belardelli, F. (2014) Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death & Differentiation. 21 (1), 15-25. Available from: Available from: doi.org/10.1038/cdd.2013.67
Ciardiello, D., Vitiello, P. P., Cardone, C., Martini, G., Troiani, T., Martinelli, E. & Ciardiello, F. (2019) Immunotherapy of colorectal cancer: Challenges for therapeutic efficacy. Cancer Treatment Reviews. 76, 22-32. Available from: doi.org/10.1016/j.ctrv.2019.04.003
Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumours. Proceedings of the National Academy of Sciences of the United States of America. 107 (9), 4275-4280. Available from: doi.org/10.1073/pnas.0915174107
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., Lennon, V. A., Celis, E. & Chen, L. (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nature Medicine. 8 (8), 793-800. Available from: doi.org/10.1038/nm730
Ebert, P. J. R., Cheung, J., Yang, Y., McNamara, E., Hong, R., Moskalenko, M., Gould, S. E., Maecker, H., Irving, B. A., Kim, J. M., Belvin, M. & Mellman, I. (2016) MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. Immunity. 44 (3), 609-621. Available from: doi.org/10.1016/j.immuni.2016.01.024
Eng, C., Kim, T. W., Bendell, J., Argilés, G., Tebbutt, N. C., Di Bartolomeo, M., Falcone, A., Fakih, M., Kozloff, M., Segal, N. H., Sobrero, A., Yan, Y., Chang, I., Uyei, A., Roberts, L., Ciardiello, F. & IMblaze370 Investigators. (2019) Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. The Lancet.Oncology. 20 (6), 849-861. Available from: doi.org/10.1016/S1470-2045(19)30027-0
Golshani, G. & Zhang, Y. (2020) Advances in immunotherapy for colorectal cancer: a
review. Therapeutic Advances in Gastroenterology. 13, 1756284820917527.
Available from: doi.org/10.1177/1756284820917527
Gryfe, R., Kim, H., Hsieh, E. T. K., Aronson, M. D., Holowaty, E. J., Bull, S. B., Redston, M. & Gallinger, S. (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. The New England Journal of Medicine. 342 (2), 69-77. Available from: doi.org/10.1056/NEJM200001133420201
Haraldsdottir, S., Einarsdottir, H. M., Smaradottir, A., Gunnlaugsson, A. & Halfdanarson, T. R. (2014) Colorectal cancer – review. Laeknabladid. 100 (2), 75-82. Available from: doi.org/10.17992/lbl.2014.02.531
Hendler, R. & Zhang, Y. (2018) Probiotics in the Treatment of Colorectal Cancer. Medicines (Basel, Switzerland). 5 (3), 101. Available from: doi.org/10.3390/medicines5030101
Kather, J. N., Halama, N. & Jaeger, D. (2018) Genomics and emerging biomarkers for immunotherapy of colorectal cancer. Seminars in Cancer Biology. 52, 189-197. Available from: doi.org/10.1016/j.semcancer.2018.02.010
Kawakami, H., Zaanan, A. & Sinicrope, F. A. (2015) Microsatellite instability testing and its role in the management of colorectal cancer. Current Treatment Options in Oncology. 16 (7), 30. Available from: doi.org/10.1007/s11864-015-0348-2
Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P. & Vandenabeele, P. (2012) Immunogenic cell death and DAMPs in cancer therapy. Nature Reviews Cancer. 12 (12), 860-875. Available from: doi.org/10.1038/nrc3380
Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. (2017) Designer vaccine nanodiscs for personalized cancer immunotherapy. Nature Materials. 16 (4), 489-496. Available from: doi.org/10.1038/nmat4822
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., Biedrzycki, B., Donehower, R. C., Zaheer, A., Fisher, G. A., Crocenzi, T. S., Lee, J. J., Duffy, S. M., Goldberg, R. M., de la Chapelle, A., Koshiji, M., Bhaijee, F., Huebner, T., Hruban, R. H., Wood, L. D., Cuka, N., Pardoll, D. M., Papadopoulos, N., Kinzler, K. W., Zhou, S., Cornish, T. C., Taube, J. M., Anders, R. A., Eshleman, J. R., Vogelstein, B. & Diaz, L. A. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 372 (26), 2509-2520. Available from: doi.org/10.1056/NEJMoa1500596
Lenz, H. -. J., Van Cutsem, E., Limon, M. L., Wong, K. Y., Hendlisz, A., Aglietta, M., Garcia-Alfonso, P., Neyns, B., Luppi, G., Cardin, D., Dragovich, T., Shah, U., Atasoy, A., Postema, R., Boyd, Z., Ledeine, J. -., Overman, M. & Lonardi, S. (2018) Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Annals of Oncology. 29, viii714. Available from: doi.org/10.1093/annonc/mdy424.019
Liu, L., Mayes, P. A., Eastman, S., Shi, H., Yadavilli, S., Zhang, T., Yang, J., Seestaller-Wehr, L., Zhang, S. Y., Hopson, C., Tsvetkov, L., Jing, J., Zhang, S., Smothers, J. & Hoos, A. (2015) The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 21 (7), 1639-1651. Available from: doi.org/10.1158/1078-0432.CCR-14-2339
Llosa, N. J., Cruise, M., Tam, A., Wicks, E. C., Hechenbleikner, E. M., Taube, J. M., Blosser, R. L., Fan, H., Wang, H., Luber, B. S., Zhang, M., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Sears, C. L., Anders, R. A., Pardoll, D. M. & Housseau, F. (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discovery. 5 (1), 43-51. Available from: doi.org/10.1158/2159-8290.CD-14-0863
Ni, Q., Zhang, F., Liu, Y., Wang, Z., Yu, G., Liang, B., Niu, G., Su, T., Zhu, G., Lu, G., Zhang, L. & Chen, X. (2020) A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer. Science Advances. 6 (12), eaaw6071. Available from: doi.org/10.1126/sciadv.aaw6071
Nosho, K., Baba, Y., Tanaka, N., Shima, K., Hayashi, M., Meyerhardt, J. A., Giovannucci, E., Dranoff, G., Fuchs, C. S. & Ogino, S. (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. The Journal of Pathology. 222 (4), 350-366. Available from: doi.org/10.1002/path.2774
Overman, M. J., Ernstoff, M. S. & Morse, M. A. (2018) Where we stand with immunotherapy in colorectal cancer: deficient mismatch repair, proficient mismatch repair, and toxicity management. American Society of Clinical Oncology Educational Book. (38), 239-247. Available from: doi.org/10.1200/EDBK_200821
Pericay, C., Gallego, J., Montes, A. F., Oliveres, H., Asensio-Mart.nez, H., Garcia-Gomez, J., Fernandez-Plana, J., Marin-Alcala, M., Ballester-Espinosa, M., Salgado,
M., Declara, I. M., Gomez-Gonzalez, L., Iglesias-Rey, L. & Cirera, l. (2018) Real world data in colorectal cancer: A retrospective analysis of overall survival in metastatic colorectal cancer patients between 2011-2015 treated in Spain, preliminary results (RWD-ACROSS study). Annals of Oncology. 29, v78. Available from: doi.org/10.1093/annonc/mdy151.276
Rekoske, B. T., Smith, H. A., Olson, B. M., Maricque, B. B. & McNeel, D. G. (2015) PD-1 or PD-L1 blockade restores antitumor efficacy following SSX2 epitope-modified DNA vaccine immunization. Cancer Immunology Research. 3 (8), 946-955. Available from: doi.org/10.1158/2326-6066.CIR-14-0206
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., Fidelle, M., Flament, C., Poirier-Colame, V., Opolon, P., Klein, C., Iribarren, K., Mondragón, L., Jacquelot, N., Qu, B., Ferrere, G., Clémenson, C., Mezquita, L., Masip, J. R., Naltet, C., Brosseau, S., Kaderbhai, C., Richard, C., Rizvi, H., Levenez, F., Galleron, N., Quinquis, B., Pons, N., Ryffel, B., Minard-Colin, V., Gonin, P., Soria, J. C., Deutsch, E., Loriot, Y., Ghiringhelli, F., Zalcman, G., Goldwasser, F., Escudier, B., Hellmann, M. D., Eggermont, A., Raoult, D., Albiges, L., Kroemer, G. & Zitvogel, L. (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.). 359 (6371), 91-97. Available from: doi.org/10.1126/science.aan3706
Sender, R., Fuchs, S. & Milo, R. (2016) Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biology. 14 (8), e1002533. Available from: doi.org/10.1371/journal.pbio.1002533
Sermer, D. & Brentjens, R. (2019) CAR T-cell therapy: Full speed ahead. Hematological Oncology. 37, 95-100. Available from: doi.org/https://doi.org/10.1002/hon.2591
Simon, K. (2016) Colorectal cancer development and advances in screening. Clinical Interventions in Aging. 11, 967-976. Available from: doi.org/10.2147/CIA.S109285
Soares, K. C., Rucki, A. A., Wu, A. A., Olino, K., Xiao, Q., Chai, Y., Wamwea, A., Bigelow, E., Lutz, E., Liu, L., Yao, S., Anders, R. A., Laheru, D., Wolfgang, C. L., Edil, B. H., Schulick, R. D., Jaffee, E. M. & Zheng, L. (2015) PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. Journal of Immunotherapy. 38 (1), 1-11. Available from: doi.org/10.1097/CJI.0000000000000062
Spranger, S., Spaapen, R. M., Zha, Y., Williams, J., Meng, Y., Ha, T. T. & Gajewski, T. F. (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Science Translational Medicine. 5 (200), 200ra116. Available from: doi.org/10.1126/scitranslmed.3006504
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A. &
Bray, F. (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. 71 (3), 209-249. Available from: doi.org/10.3322/caac.21660
Taube, J. M., Anders, R. A., Young, G. D., Xu, H., Sharma, R., McMiller, T. L., Chen, S., Klein, A. P., Pardoll, D. M., Topalian, S. L. & Chen, L. (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science Translational Medicine. 4 (127), 127ra37. Available from: doi.org/10.1126/scitranslmed.3003689
Tondini, E., Arakelian, T., Oosterhuis, K., Camps, M., van Duikeren, S., Han, W., Arens, R., Zondag, G., van Bergen, J. & Ossendorp, F. (2019) A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. Oncoimmunology. 8 (11), 1652539. Available from: doi.org/10.1080/2162402X.2019.1652539
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., West, A. N., Carmona, M., Kivork, C., Seja, E., Cherry, G., Gutierrez, A. J., Grogan, T. R., Mateus, C., Tomasic, G., Glaspy, J. A., Emerson, R. O., Robins, H., Pierce, R. H., Elashoff, D. A., Robert, C. & Ribas, A. (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515 (7528), 568-571. Available from: doi.org/10.1038/nature13954
Von Hoff, D. D., Layard, M. W., Basa, P., Davis, H. L.,Jr, Von Hoff, A. L., Rozencweig, M. & Muggia, F. M. (1979) Risk factors for doxorubicin-induced congestive heart failure. Annals of Internal Medicine. 91 (5), 710-717. Available from: doi.org/10.7326/0003-4819-91-5-710
Whiteside, T. L. (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene. 27 (45), 5904-5912. Available from: doi.org/10.1038/onc.2008.271
Zhu, G., Lynn, G. M., Jacobson, O., Chen, K., Liu, Y., Zhang, H., Ma, Y., Zhang, F., Tian, R., Ni, Q., Cheng, S., Wang, Z., Lu, N., Yung, B. C., Wang, Z., Lang, L., Fu, X., Jin, A., Weiss, I. D., Vishwasrao, H., Niu, G., Shroff, H., Klinman, D. M., Seder, R. A. & Chen, X. (2017) Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy. Nature Communications. 8 (1), 1954. Available from: doi.org/10.1038/s41467-017-02191-y