Blocking checkpoint proteins enhance immune cell activity
In healthy individuals, the immune system is intricately regulated to maintain homeostasis. Consider it as a see-saw: on the one hand, excessive immune activation in the absence of harmful pathogens may manifest as autoimmune diseases; on the other hand, inadequate immune defense creates vulnerability during infections. The immune checkpoint is one mechanism that helps balance the see-saw. One such checkpoint protein, programmed death 1 (PD-1), is found on the surface of B and T cells. As its name suggests, PD-1 initiates cell death upon binding to its partner, conveniently named programmed death-ligand 1 (PD-L1). In healthy individuals, cells express PD-L1 to eliminate self-reactive immune cells, thereby preventing autoimmunity. Unfortunately, cancer cells, which are also arguably self, often upregulate checkpoint proteins like PD-L1 to improve their survival.
Having understood the importance of this mechanism in cancer cell survival, researchers developed monoclonal antibodies against checkpoint proteins to block their interactions. This in turn stops the apoptotic signaling in anti-tumor immune cells and promotes their tumor-killing activity. Such anti-PD-1 treatments have been developed for the treatment of various cancers, such as melanoma.
Dostarlimab is effective against deficient mismatch repair rectal cancer
Cercek and colleagues at the Memorial Sloan Kettering Cancer Center achieved an astounding 100% success in a cancer immunotherapy study with dostarlimab. Dostarlimab is an anti-PD-1 monoclonal antibody that was previously approved in 2021 for the treatment of endometrial cancer with deficient mismatch repair (dMMR). During cell divisions, the DNAs in the nucleus must replicate to pass the genetic code to each of the daughter cells. However, a few errors inevitably happen when cells are replicating this vast library of over 6 billion base pairs. So how do we not have abnormal cells throughout our body? Mismatch repair is one process that recognizes and corrects such DNA replication errors. dMMR increases mutations and thereby significantly increases the risk of cancer development.
This clinical trial targets a specific subset of locally advanced rectal cancer patients with dMMR. It is especially important to develop new therapies for dMMR rectal cancer because it responds poorly to currently available chemotherapy. As a phase II trial, this study is designed to evaluate whether the treatment is effective for this specific cancer type using a relatively small sample of patients. Promising phase II results would prompt for subsequent phase III study with more patients before the drug will be submitted to Food and Drug Administration for approval.
At the time of the publication, 12 patients had completed the 6-month treatment of dostarlimab, given once every 3 weeks. These patients’ cancer status was assessed at the baseline, 3 months, 6 months, and then every 4 months after the start of the treatment. The researchers initially planned to follow the dostarlimab treatment with standard chemoradiotherapy and surgery. To the researchers’ surprise, the tumor was undetectable in the majority of these patients as early as 6 weeks after the start of therapy! These patients experienced only mild adverse events such as dermatitis, fatigue, and nausea following the drug administration. These adverse effects were unsurprising because checkpoint inhibitors do increase the risk of diseases that may have autoimmune nature. By the end of the 6 months, there was a 100% treatment success among the 12 patients, thus preventing the need for chemoradiotherapy and surgery. These patients have been continuously monitored and showed no signs of cancer recurrence or progression so far.
Further investigation is necessary
This is a groundbreaking therapeutic advancement because the standard treatment was associated with significant adverse effects including infertility, bowel, and sexual dysfunction, in addition to the remission in some patients. This is particularly important because rectal cancer is becoming increasingly prevalent among young adults. In fact, 3 of the 12 patients that completed this study at the time of publication are 30 years old or younger. Although the result of this study is incredibly promising, the sample size of Phase II studies is generally fairly small. This therapeutic success needs to be replicated in Phase III at other healthcare centers and with a more diverse and larger patient population.
While checkpoint inhibitors like dostarlimab have been used for a variety of cancer treatments, the efficacy seen in this study is unprecedented. It is important to understand that the success of dostarlimab in dMMR rectal cancer may not be extrapolated to other forms of cancers. Nonetheless, the researchers noted that their decision to administer dostarlimab over 6 months as opposed to short-term treatment in earlier studies may have contributed to their success. Therefore, it remains an important mystery why these localized mismatch repair-deficient rectal cancers are particularly responsive to the treatment.
Cercek, A., Lumish, M., Sinopoli, J., Weiss, J., Shia, J., Lamendola-Essel, M., El Dika, I. H., Segal, N., Shcherba, M., Sugarman, R., Stadler, Z., Yaeger, R., Smith, J. J., Rousseau, B., Argiles, G., Patel, M., Desai, A., Saltz, L. B., Widmar, M., … Diaz, L. A. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. The New England Journal of Medicine. 2022 June; https://doi.org/10.1056/NEJMoa2201445
Article author: YongGuang Jiang. Yong is an IRTA postbaccalaureate fellow at the National Institute of Health. His research is focused on studying the role of plasmin and neutrophil elastase in hematopoietic recovery.
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