Introduction
Cancer is very often placed at the forefront of medical research and with an estimated 1 in 2 people expected to develop cancer at some point in their lives1 it is becoming increasingly important that novel drugs and therapies are discovered to mitigate the impacts. Over the years, we have seen the development of powerful treatment methods, from chemotherapy to radiotherapy, however more recently there has been a rise in the use of immunotherapy. One recent form of immunotherapy, a drug called Dostarlimab, has taken the medical world by storm after a small study reported a 100% complete clinical response.
How does it Work?
The drug works by enhancing the body’s immune response against tumour cells. It does this through two types of proteins PD-L1 and PD-L2 (programmed death ligand 1 and 2) which typically play a role in weakening our immune response when bound to a complementary receptor on a T-cell. This plays an important physiological role in preventing excessive destruction to non-harmful cells, as well as preventing the onset of autoimmune diseases.2
However, some tumour cells express these proteins on their surface, which when bound to a T-cell inhibits the cell-mediated immune response, and the cancer cells remain undestroyed.3 Dostarlimab is a monoclonal antibody which binds to PD-1, the complementary receptor on the T-cell, and therefore prevents the interaction between the tumour and T-cells. This enables both identification and reactivates cytotoxic activity, allowing the cancer cells to be attacked.
Fig: Images showing the interactions without (left) and with (right) Dostarlimab3
Usage of the Drug
Although the drug has only recently risen to fame in mainstream media, the drug had already begun rollout across the NHS in February 2022 as a treatment method for endometrial cancer.4 Alternative options such as surgery and chemotherapy tend to be more invasive and often leave patients with a poor prognosis, which is why Dostarlimab serves as an innovative drug. It requires only four half-an-hour sessions over a 12 week-period, offering patients quicker, safer and more effective treatment.
It was only more recently that a small trial involving 12 rectal cancer patients saw a 100% remission rate.5 The patients involved suffered from a particular subset of rectal cancer caused by mismatch repair deficiency (cells with many DNA mutations), which is affected by blockage of the PD-1 receptor on T-cells caused by Dostarlimab. Despite the small sample size, a high confidence interval of 95% and no severe side effects suggest that the drug holds a lot of potential.
Limitations of the Drug
Despite the fact that the drug has only been proven effective on one particular form of the disease, it is estimated that 5-10% of rectal cancers are due to mismatch repair deficiency6. With over 700,000 people diagnosed with rectal cancer each year7, even a small proportion of those cases being treated represent a significant triumph.
However, the results of this trial must not be taken as a definitive yes for the use of Dostarlimab, as a follow-up study with a larger sample size would increase the validity and reliability of the study. Additionally, the patients were followed up for between 6 to 25 months 5 in order to assess any recurrence, but ideally, longer follow-up times would allow researchers to better ascertain the long term efficacy. A further obstacle which may hinder large scale roll out is cost, which is particularly a challenge in countries where private healthcare is dominant. According to the New York Times8, each dose cost $11,000 and with several doses required over a 6 month period, the drug may prove to be unaffordable for many.
Such limitations are not completely restricting, as numerous solutions exist to tackle them. For example, subsidies from the government would not only allow for larger studies to be completed, but also increase research in cost reduction. Whilst this presents an opportunity cost to a country’s government, extra funding for the healthcare sector leads to better survival rates, which benefits the economy, hence creating a positive multiplier effect.
Conclusion
The future of Dostarlimab seems to be exciting and may change the way in which we treat rectal cancer. Not only is it an innovative way in which to treat cancer, it’s potential benefits to the fields of endometrial and mismatch repair deficiency cancers are immense. However, in the near future, further trials, or extensions of ongoing ones, are warranted in order to successfully determine whether the drug is a viable treatment method, as well as solutions which address cost reduction.
The unprecedented results of the trial have been groundbreaking for the medical sector, and provide a great sense of hope that we will continue to discover cancer treatments. Nonetheless, whether it proves to be a miracle cure or not, it is fair to say that immunotherapy in itself has been revolutionary to the world of medicine, and the research gained from such studies conducted will prove to be valuable in the long term.
Nyneisha Bansal, Youth Medical Journal 2022
References
1. Cancer [Internet]. nhs.uk. 2022 [cited 15 June 2022]. Available from: https://www.nhs.uk/conditions/cancer/
2. Touboul R, Bonavida B. YY1 expression and PD-1 regulation in CD8 T lymphocytes. YY1 in the Control of the Pathogenesis and Drug Resistance of Cancer. 2021;:289-309.
3. How JEMPERLI works [Internet]. Jemperli. 2022 [cited 15 June 2022]. Available from: https://www.jemperlihcp.com/mechanism-of-action/
4. England N. NHS England » New life-extending drug for advanced womb cancer to be rolled out on the NHS [Internet]. England.nhs.uk. 2022 [cited 15 June 2022]. Available from: https://www.england.nhs.uk/2022/02/new-life-extending-drug-for-advanced-womb-cancer-to-be-rolled-out-on-the-nhs/
5. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New England Journal of Medicine. 2022;.
6. Promising rectal cancer study [Internet]. ScienceDaily. 2022 [cited 15 June 2022]. Available from: https://www.sciencedaily.com/releases/2022/06/220605130358.htm#:~:text=A%20scientist%20comments%20on%20the,a%20subtype%20of%20rectal%20cancer.
7. Colorectal Cancer – Statistics [Internet]. Cancer.Net. 2022 [cited 15 June 2022]. Available from: https://www.cancer.net/cancer-types/colorectal-cancer/statistics#:~:text=These%20numbers%20include%20106%2C180%20new,with%20colorectal%20cancer%20in%202020.
8. Kolata G. A Cancer Trial’s Unexpected Result: Remission in Every Patient [Internet]. Nytimes.com. 2022 [cited 15 June 2022]. Available from: https://www.nytimes.com/2022/06/05/health/rectal-cancer-checkpoint-inhibitor.html
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