By: Sairah Sheikh, PharmD Candidate c/o 2024
Promising new research conducted by doctors at Memorial Sloan Kettering Cancer Center showed 100% remission of rectal cancer in 12 patients after immunotherapy. Traditionally, patients with rectal cancer are treated with chemotherapy and radiation, followed by a surgical resection of the rectum.1 However, this method carries the risk of many adverse outcomes, including severe bowel, bladder, and sexual dysfunction; infertility; and altered quality of life. Physicians have reported a disturbing uptick in rectal cancer diagnoses in young adults, primarily between the ages of 20 to 50.2 New immunotherapy options may be more appealing over traditional chemotherapy, offering better efficacy and side effect profiles.
In this phase 2 study conducted by Cercek et al., doctors alternatively used an experimental immunotherapy drug called dostarlimab, an anti-PD-1 monoclonal antibody.1 Dostarlimab works by inhibiting programmed cell death-1 (PD-1). PD-1 is a protein found on T cells that regulates the body’s immune response. Inhibition of PD-1 releases regulation of the immune system, allowing T cells to attack cancer cells.3 Dostarlimab 500 mg was administered via intravenous infusion every three weeks for six months in 12 patients. The original protocol called for follow up treatment with chemoradiotherapy and surgery unless patients achieved a complete clinical response. A complete clinical response was defined as the absence of residual disease on digital and endoscopic rectal examination and on rectal MRI. After the study period, all 12 patients were deemed 100% free of their rectal cancer.1
The patients in this study all had mismatch repair-deficient (dMMR) stage 2 or 3 rectal adenocarcinoma. The DNA mismatch repair system is normally able to identify and repair mismatched nucleotides during genetic recombination or from damage caused by external physical or chemical insults. dMMR can originate from germline mutations in DNA mismatch repair genes. Unrepaired nucleotide sequences increase the risk of multiple cancers, but are most commonly associated with colorectal cancer.4 About 5-10% of all rectal cancer patients have dMMR.5
Immunotherapy becomes a critical option in treating dMMR locally advanced rectal cancer. Certain cellular mutations accumulate in dMMR tumors, which normally would stimulate the immune system. To evade detection, cancer cells may produce PD-1 to down-regulate the immune response. Immunotherapy agents, like dostarlimab, are used as checkpoint inhibitors to block the PD-1 receptor, restoring the T cell’s ability to recognize heavily mutated dMMR tumors and facilitate an immune response.5
In addition to dMMR tumors, rectal cancers may also fall under additional subtypes. One subtype is known as consensus molecular subtype 4 (CMS4) tumors. In these patients, T cells are activated, but cannot attack the tumor cells. Under a microscope, the CMS4 tumor microenvironment can be seen clustered with the presence of T cells and macrophages. CMS4 cancers are often diagnosed at advanced stages and have a poor prognosis.6,7 Other subtypes include CMS2 or CMS3 tumors, where the immune system shows little activity. For these subtypes, research is less focused on the tumor microenvironment and more focused on developing treatments to help the immune system recognize proteins created from tumor mutations.6 One potential solution could be through chimeric antigen receptor (CAR) T cell therapy. CAR T cell therapy is a type of immunotherapy where T cells are taken from a patient and are genetically modified in a lab to produce receptors that recognize antigens on the surface of cancer cells. The T cells are then multiplied and put back into the patient where they can identify and attack cancer cells.6
Although plenty of groundbreaking research is being conducted on colorectal cancer, some findings are not as pleasant. As mentioned before, studies are showing an increased prevalence of rectal cancer in younger patients. A 2018 study by the American Cancer Society estimated that those born in 1990 have two times the risk of colon cancer and four times the risk of rectal cancer compared to those born in 1950.2 Unfortunately, the death rate for younger patients with colorectal cancer is increasing. The causes behind this trend remain unknown, but some hypothesized risk factors include inactive lifestyles, low-fiber diets, obesity, and regular use of alcohol, tobacco, and illicit drugs. The study acknowledged that adults over 55 years old are still more likely to get colorectal cancer, however, patients younger than 55 years old are 58% more likely to be diagnosed with advanced cancer.2 It is advised that if a patient experiences persistent rectal bleeding, changes in bowel movements, or unexplained and frequent abdominal pain or gas, they should reach out to their physician and look to schedule a colonoscopy. It is also recommended that Americans get periodic screenings for colorectal cancer starting at age 45 rather than the previous recommendation of age 50, regardless of whether they have symptoms or not.2
With the rise in number of younger patients getting aggressive forms of colorectal cancer, research on this disease has never been more pivotal. Institutions like Memorial Sloan Kettering Cancer Center are finding more efficacious alternatives to chemotherapy and radiation, avoiding detrimental adverse effects. Instead, immunotherapy treatments like dostarlimab are coming into the spotlight, allowing patients to avoid the toxicities of chemotherapy and have improved odds of living enriched lives.
- Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer: Nejm. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2201445. Published June 23, 2022. Accessed August 21, 2022.
- Katella K. Colorectal cancer: What gen-XERS and Millennials Need To Know. Yale Medicine. https://www.yalemedicine.org/news/colorectal-cancer-in-young-people. Published February 2, 2022. Accessed August 22, 2022.
- NCI Dictionaries. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/pd-1. Accessed October 31, 2022.
- Shaikh T, Handorf EA, Meyer JE, Hall MJ, Esnaola NF. Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults. JAMA Oncol.2018;4(2):e173580. doi:10.1001/jamaoncol.2017.3580
- Rectal cancer disappears after experimental use of immunotherapy. Memorial Sloan Kettering Cancer Center. https://www.mskcc.org/news/rectal-cancer-disappears-after-experimental-use-immunotherapy. Published June 5, 2022. Accessed August 21, 2022.
- Carter D. Immunotherapy and colorectal cancer: Where we are and what’s ahead. MD Anderson Cancer Center. https://www.mdanderson.org/cancerwise/can-immunotherapy-treat-colorectal-cancer–where-we-are-and-what-is-ahead.h00-159459267.html. Published March 10, 2021. Accessed August 21, 2022.
- Thanki K, Nicholls ME, Gajjar A, et al. Consensus Molecular Subtypes of Colorectal Cancer and their Clinical Implications. Int Biol Biomed J. 2017;3(3):105-111.