What is Dostarlimab?
A humanized monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed cell death 1 (PD-1; programmed death-1), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, dostarlimab-gxly binds to and inhibits PD-1 and its downstream signaling pathways. This may restore immune function through the activation of T cells. PD-1, a transmembrane protein in the Ig superfamily expressed on T cells, functions as an immune checkpoint protein that negatively regulates T-cell activation and T-cell-mediated immune responses when activated by its ligands programmed cell death receptor ligand 1 (PD-L1) or 2 (PD-L2); it plays an important role in tumor evasion from host immunity.
Who Makes Dostarlimab?
Doctors and patients from the bowel cancer trial, from left: Sascha Roth, Dr Luis Diaz, Imtiaz Hussain, Dr Andrea Cercek, Avery Holmes and Nisha Varughese (Image: Memorial Sloan Kettering Cancer Center)
Developed by a biotech company out of Massachusetts called Tesaro before being acquired by GlaxoSmithKline in 2019, dostarlimab is also known by the brand name Jemparli.
First approved in the United States for use as a cancer treatment in early 2021, dostarlimab is a monoclonal antibody.
How does Dostarlimab work?
Dostarlimab, marketed by GlaxoSmithKline, is a type of monoclonal antibody that blocks proteins called checkpoints which are made up of immune system cells, such as T cells, and some cancer cells.
These checkpoints help keep immune responses from acting too strong and may prevent T cells from killing cancer cells. When these checkpoints are blocked, T cells are free to kill cancer cells more efficiently.
Examples of checkpoint proteins found on T cells or cancer cells include PD-1, PD-L1, CTLA-4 and B7-1. Some immune checkpoint inhibitors, called PD-1 inhibitors, are already used to treat various types of cancers.
What Are Monoclonal Antibodies?
Monoclonal antibodies like dostarlimab are laboratory-made antibodies design to fight specific illnesses.
The term became more widely known in the last two years as a variety of monoclonal antibodies came out to treat COVID-19.
Dostarlimab is specifically designed to block a particular protein involved in cancer cells called PD-1.
In the Memorial Sloan Kettering trial with rectal cancer, all of the patients' tumors also had a feature known as mismatch repair deficiency.
What Is Mismatch Repair Deficiency?
Cells that have mutations that keep them from fixing mistakes when DNA is copied are said to have "mismatch repair deficiency."
Having mismatch repair deficiency can be associated with cells becoming cancerous.
Will Dostarlimab work against all cancers?
That's where the catch lies. According to oncologist and cancer researcher Dr Aju Mathew, who is associated with the Ernakulam Cancer Centre in Kerala, drugs based around the fundamentals of PD-1 inhibitors, like dostarlimab, can be used only in patients with the genetic property of mismatch repair (MMR) deficiency.
These patients are identified based on genetic or cytology tests, and have cells with mutations or changes in certain genes involved in correcting mistakes made when DNA is copied in a cell.
MMR deficient cells normally have many DNA mutations, which may lead to cancer but estimates indicate that less than 10 percent of colon cancer patients may have MMR deficiency.
But while MMR deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, it may also be seen in patients with breast, thyroid, prostate and bladder cancer.
All You Need to Know About Dostarlimab Trial
The trial included 18 cancer patients who took a drug called ‘Dostarlimab’ for around six months, and by the end of it, every one of them got rid of their tumours, reported the New York Times.
As per the NYT, the 18 patients had undergone various treatments before for cancer including chemotherapy, radiation, and invasive surgery. The patients had reportedly undergone the US trial expecting to have to go through other procedures in the next step. However, no further treatment was needed.
According to experts, the drug ‘Dostarlimab’ includes laboratory-produced molecules and acts as substitute antibodies in the human body. As per experts, cancer is undetectable by physical exam - proving that the drug could be a potential cure for the disease. Dr Luis A. Diaz J. of New York's Memorial Sloan Kettering Cancer Center said this was “the first time this has happened in the history of cancer,” reported ANI.
The patients took the drug Dostarlimab every three weeks for six months during the trial. Notably, all the patients were in the similar stages of cancer and had not spread to other organs.
According to experts, the trial has been “shocking” and “unheard of”. Oncologist Dr Andrea Cercek described the moment patients found out they were cancer-free: “There were a lot of happy tears”, she said, as quoted by the NYT.
At the time of the presentation 18 patients had been accrued to the trial. A majority were women (67%) and had a median age of 54 years (range, 26-78). In terms of tumor staging 22% had T1/2 tumors and 78% had T3 or T4 tumors. The mean tumor mutational burden was 67 mut/Mb (range, 36-106).
The first 2 patients enrolled and treated with dostarlimab. The first patient was a woman aged 38 years who presented with a large, node-positive tumor. “After completion of 6 months of [dostarlimab], we noted disappearance of tumor on endoscopy, and no evidence of tumor on MRI; she achieved a cCR, which was a very exciting start to the trial.”
The second patient was a woman aged 30 years who presented with approximately 3 months of rectal bleeding, a change in the caliber of her stool, and pelvic pain for approximately 2 weeks prior to diagnosis. “After just 2 doses, she felt significantly better, her bowels had normalized, and she no longer had pelvic pain. At 3 months, she achieved a cCR [on endoscopy] and on MRI she had a near complete response, so there was still some visible tumor there. On PET [evidence of disease] had also completely disappeared. Her final examination, after completion of 6 months of therapy was notable for a cCR and I’m very happy to say that this has been sustained now in follow-up for nearly 2 years.”
In August 2021, dostarlimab was approved by the FDA for the treatment of patients with dMMR recurrent or advanced solid tumors who have progressed on or following prior therapy and who have no satisfactory treatment options.3
“Neoadjuvant dostarlimab for 6 months represents a promising new treatment for patients with stage II/III dMMR rectal cancer [and] larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival end points are needed,” Ng said. “It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatment for our patients.”
The findings of the small clinical trial, published in the New England Journal of Medicine and shared in a representation during a recent meeting of the American Society of Clinical Oncology, said that the drug worked like a wonder in mismatch repair-deficient stage II or III rectal cancer patients without metastasis.
Dr Nitesh Rohatgi, senior director, medical oncology, Fortis Memorial Research Institute in Gurugram, pointed out that this was a theory put to the test where patients who were yet to undergo surgery for colon cancer and had something called microsatellite instability or the condition of genetic predisposition to mutation that results from impaired DNA MMR.
During this research, dostarlimab was administered every three weeks for six months in patients and was planned to be followed by standard chemoradiotherapy and surgery.
But the 12 patients who completed the course did not need any follow-up treatment during the study period (further follow-up is still on).
Dr Parveen Jain, head of the oncology department at Aakash Healthcare in Delhi, said that immunotherapy agents, such as dostarlimab, are better tolerated than conventional chemotherapy.
“This is the first time an immunotherapy agent — and in fact any anti-cancer treatment — has achieved a 100 percent complete remission rate,” he said.
Is it really the miracle cancer drug everyone has been hoping for?
Mathew says that a number of his patients have flooded him with queries over the last few days asking if the drug, which is being projected as a wonder cure for cancer, is going to be available in India soon and may be suitable for them.
“I am happy about the promising results from a research trial but we need to understand that it is a very small trial and has worked in patients with a very specific type of cancer,” he told Moneycontrol.
Both Mathew and Rohatgi said that they have been using immunotherapy to treat many patients but in specified types of cancer.
Dr CS Pramesh, director of the Tata Memorial Centre in Mumbai, pointed out on Twitter that to call dostarlimab a ‘miracle cure’ that would impact cancer treatment globally would be “premature and fanciful”.
While the study findings may be exciting, he wrote, a much higher number of patients need to be treated, followed up and the results evaluated from a large phase 3 randomised trial before the drug could be called “practice-changing”.
Rohtagi said that for now, the only implication of the new research findings may be that patients with colon cancer and microsatellite instability can undergo immunotherapy before surgery.
Dr Sewanti Limaye, director, precision and medical oncology at Sir HN Reliance Foundation hospital in Mumbai, pointed out that the message from the trial may be to carry out genomic analysis, understand the biology of the cancer and figure out specific treatment for a patient’s specific problem.
In general, immunotherapy is recommended for cancers caused by a mismatch repair problem. This treatment activates our body's immune system against cancer. It exploits the potential of PD1 protein, which plays a vital role in the body's immune system. As the mismatch repairing cancer progresses, our active immune system becomes completely dormant. Especially T cells in the immune system. This treatment involves the stimulation of T cells by PD1 blockade and the invasion of the cancerous area. That is if the body is assumed to be a car, the system, including the brakes, is the immune system. It is like saying the brakes must be applied correctly in the event of an accident. The PD1 blockade activates the breaking mechanism of T cells.
PD1 blockade treatment is not something new. There is already a treatment that can effectively treat cancer through this method after surgery. This method is also used in cases where the cancerous tissue has spread through the blood to other organs and caused second cancer (metastasis). However, researchers at MSKCC have discovered that the treatment with PD1 blockade can stave off cancer by avoiding surgery. Also, the study suggests that this therapy may be beneficial in the case of all types of mismatch-repairing cancers. The advantage is a much faster cure and fewer side effects than other therapies.
Medication, treatment, and monitoring
Dostarlimab is a synthetic (monoclonal) antibody that has the ability to build strong immunity against a pathogen. The drug should be given once in 3 weeks for 6 months. Researchers claim that results will be visible in a few days. Accordingly, 81% of symptoms may change within 9 weeks of the treatment. They were monitored for 6 to 25 months after completing the course to confirm that cancer had completely vanished. Follow-up treatment does not detect the risk of cancer recurrence or development – MSKCC.
Avoid chemo and radiation
Radiation therapy and chemotherapy are two of the most widely used treatments for cancer. Radiation therapy eliminates and shrinks cancer cells by providing significant radiation. This does not completely eliminate the cancer cells. Therefore, treatment can extend for weeks. It has its own side effects as it also destroys the healthy cells in an attempt to destroy the cancer cells. However, chemo treatment involves the use of drugs that kill cancer cells, and it can completely stop the growth of cancer cells and inhibit growth. This too can have serious side effects.
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