Increasing Natural Killer Cell Potency in Pancreatic Cancer

An idea utilizing an inhibition of butyrate uptake in NK cells to strengthen their effector function, a solution tackling pancreatic cancer

PDAC cells shown under a microscope (Source: University of Minnesota, Cancer Bioengineering Initiative)

Abstract

Based on previous studies, it has been shown that the microbiome plays a role in the progression of pancreatic ductal adenocarcinoma (PDAC). This is modulated by peripheral natural killer cells as an intact intestinal microbiome was shown to lower NK cell tumor infiltration in mice. The mechanism for this is suggested in this article as being mediated through the short-chain fatty acid (SCFA) butyrate. This chemical has been shown to reduce cytokine production and cytotoxicity of NK cells, with the cytokine levels of IFN-γ and perforin being decreased in both the microbiome-modulated NK cells as well as the butyrate-modulated ones. The idea proposed in this article consists of the inhibition of monocarboxylate transporter 1 (MCT1) as butyrate enters NK cells through this transport protein. Through several studies, it can be strongly reasoned that this will lead to increased NK cell activity to reduce PDAC progression.

Credit: Biorender.com

Introduction

In the past couple of years, many innovative therapies have been designed to tackle some of the most challenging diseases. One class of these treatments is immunotherapy, modifying your immune system to recognize diseases better. For example, CAR-T cell therapy has become popular for treating acute lymphoblastic leukemia. With new treatments like CAR-NK therapy on the rise as well, it is only a matter of time before we start tackling even more challenging problems. In this article, I will discuss an idea that tackles one of the deadliest cancers we know.

Pancreatic Ductal Adenocarcinoma (PDAC)

PDAC is the most prevalent form of pancreatic cancer and makes up over 90% of all cases. While pancreatic cancer itself is relatively rare, it is extremely deadly, being the third leading cause of cancer-related death in the United States. With a less than 10% 5-year survival rate for patients with PDAC, there are not many effective treatments available. This combined with its low detection rate creates very stark outcomes for patients.

PDAC forms through various genetic mutations that often mimic pancreatic development. For example, one of the changes common in almost all cases of PDAC is the activation of the Kras oncogene, normally silenced after the formation of the pancreas. This promotes the creation of a PanIN lesion, the first step to the development of PDAC. After various other mutations, which can differ from patient to patient, PDAC is fully formed.

PDAC is often staged according to its resectability, or in other words its ability to be surgically removed. It can be split into three sections: resectable, borderline resectable, or unresectable. If the tumor is considered resectable, it can be surgically removed. Borderline resectability is when the tumor is touching important arteries or veins, but not to the point where surgery is impossible. If the tumor is unresectable, this means that the tumor has grown too far into blood vessels or has metastasized to other organs.

Unfortunately, most patients usually have their PDAC diagnosed when symptoms like jaundice are prevalent, which only occur in late-stage PDAC. This is the reason why treatment is so challenging compared to cancers that were found earlier. However, as research expands to different, unexplored areas of the human body, newer mechanisms for the growth of PDAC will be discovered.

The Microbiome’s Effect on PDAC

The human microbiome is an environment of different bacteria and other living organisms that have coevolved inside our body. They are primarily located inside the intestinal lumen and have various functions in our body. Many bacteria have a symbiotic relationship with our body and can do things like produce vitamin K for our bodies from the food we eat.

However, these bacteria in particular have had to set up defenses against our immune system to prevent our body from killing them. This is done through many regulatory components such as immunosuppressive compounds and special inhibitory molecules called PAMPs. Normally, this is a net benefit to the body as it keeps our immune system from constantly inflaming our intestines and killing off our good bacteria. However, in the case of cancer, this may be a negative as suppressing immune cells can reduce their ability to infiltrate the tumor microenvironment.

Researchers at the University of Florida, Qin et al., hypothesized that this could be the case with natural killer cells in PDAC. When they compared mice who had an intact microbiome, compared with mice who had been given antibiotics, the researchers found that the mice “with an intact microbiota had a 57.4% reduction in intratumoral NK cell infiltration.” NK cells have been noted for their anti-tumor capabilities and this study highlights this.

“In this study, we demonstrate that the gut microbiota inhibits intratumoral NK cell infiltration and activation with resultant increased PDAC progression. NK cells are important for gut microbiota-mediated PDAC progression in immunodeficient and immunocompetent murine models given that antibody-mediated NK cell depletion in both models resulted in advanced tumors despite the lack of a microbiota in antibiotic-treated mice.”

Now that it is known the microbiome drives the development of PDAC, it should be asked: what specific part of the microbiome is driving this? While eliminating the microbiome seems like it could be a way to help PDAC patients, it has too many important functions that could even worsen the patient’s case. For this reason, it is necessary to look for a more specific solution that will have the intended effect.

The Production of Butyrate by the Microbiome

Butyrate, or butanoate, is an organic ion with the chemical formula C4H7O2. Bacteria produce it in the microbiome due to the fermentation of dietary fiber. Two of the most prominent bacteria in the microbiome, Faecalibacterium prausnitzii and Eubacterium rectale, which combined make up 27% of all fecal gut microbiota, have a major role in butyrate production.

Butyrate is produced from dietary fiber, which is a carbohydrate made up of many monomers. After it passes through the digestive tract and into the colon, the aforementioned bacteria will start the fermentation process which breaks down this fiber. The process that most bacteria use is as follows:

1. Dietary fiber is broken down into simpler substrates such as hexoses and pentoses by the bacteria’s enzymes called glycoside hydrolases.
2. Once the hexoses and pentoses enter the bacterial cytoplasm, they are degraded into pyruvate. The pyruvate is then converted to acetyl-CoA.
3. Acetyl-CoA is converted to butyryl-CoA until finally, butyryl-CoA is converted to butyrate by a butyrate kinase or butyryl-CoA:acetate-CoA transferase.

The release of butyrate from the bacteria as a byproduct of this fermentation has several effects, one of which is critical to this idea.

The Effect of Butyrate on NK Cells

Recently, Zaiatz-Bittencourt et al. ran a study in which NK cells stimulated by the cytokines IL-12 and IL-15 were exposed to butyrate in culture. What the researchers found is that NK cells had reduced levels of the activating receptors TRAIL, NKp44, NKp30, and NKG2D in response to butyrate stimulation. With a lower level of activating receptors, NK cells cannot exhibit their anti-tumor properties nearly as well.

Another role of NK cells is signaling other parts of the immune system when there is distress. This is done through the use of cytokines. In the same study, the researchers found that the crucial cytokines IFNγ, TNF-α, IL-22, and granzyme B were all greatly reduced when NK cells were exposed to butyrate. With lower expression of cytokines, NK cells are unable to communicate distress to other parts of the immune system, creating a more viable environment for tumors.

Finally, the researchers tested how NK cell metabolism is affected by butyrate. This process is regulated by the mTORC1, c-Myc, and HIF1-α dependent signaling pathways. When the NK cells were exposed to butyrate, it disrupted the first two signaling pathways. This creates a situation where the “energy” of the NK cells to fight off tumors is lowered and they get exhausted (which is common in immune cells) more easily.

These three effects that were studied have drastic consequences on the ability of NK cells to fight PDAC. From what has been looked at here, it can be correlated that the production of butyrate from the microbiome is one cause for the progression of PDAC through lowered NK cell function. Therefore, the solution to this problem is to inhibit the effect of butyrate on NK cells using our knowledge of how it enters the cell.

NK Cell-Specfic Inhibition

A group of solutions that don’t work is inhibiting butyrate from entering all cells in the body. This includes ideas like using antibiotics, or butyrate-neutralizing molecules as these would not specifically affect NK cells.

This is important for two reasons: butyrate-dependent metabolism, as well as its variable effects on different cells.

Colonocytes, differentiated cells in the colon, require butyrate as one source of their energy. When butyrate enters these cells, it undergoes rapid β-oxidation and can then enter the TCA cycle inside mitochondria to produce ATP for the cell’s energy. If butyrate was inhibited from these cells, the colonocytes would lose their primary energy source, as butyrate metabolism is used for 70% of ATP production in these cells.

The reason that we can afford to inhibit butyrate from NK cells is that they follow a different metabolism, the one that most of you are probably familiar with, glycolysis. This is the main reason why butyrate has the effects that it does on NK cells.

When scientists were researching the effects of butyrate on colon cancer cells, they found that butyrate slowed proliferation in these cells. However, healthy colonocytes did not seem to have these effects and instead proliferated more quickly. This was dubbed the butyrate paradox for how it has the opposite effect in cancer versus normal cells. Researchers eventually discovered that the reason for this paradox is because of metabolism. When colonocytes transform into cancerous cells, they also switch their method of ATP production, from butyrate-dependent to glycolytic. This allows the butyrate to stay unchanged in the cancer cell, leading to its effects.

The second reason we need NK cell specificity is because certain cells benefit from exposure to butyrate. It has been shown that cytotoxic T lymphocytes are positively stimulated by butyrate molecules with the expression of more effector molecules. This greatly improves their ability to fight tumors, quite opposite to the NK cells. For this reason, NK cells must be specifically targeted in this solution.

Targeting MCT1 to Inhibit Butyrate Uptake

Monocarboxylate transporter 1 (MCT1) is a proton-link plasma membrane transporter responsible for the uptake of butyrate by many different cells, including NK cells. However, this transporter is also responsible for the transport of several other molecules, including lactate, pyruvate, acetoacetate, β-hydroxybutyrate, XP13512, and GHB.

While this would normally be an issue, there is already a solution in place: MCT4. This is a similar transporter that is used to transport molecules of similar structure. This transport protein can intake the following molecules: lactate, pyruvate, acetoacetate, and β-hydroxybutyrate. Even better, this transporter does not intake butyrate. If MCT1 is inhibited, every molecule except for XP13512 and GHB can be transported while still inhibiting butyrate.

Fortunately, as of right now, XP13512 and GHB do not have any effect on NK cells. XP13512 is a clinical drug that does not have immunomodulatory effects on NK cells. Therefore, its inhibition is negligible. Furthermore, GHB is a neurotransmitter that is present in the body in low concentrations. Despite this, it is also a drug that has been abused. It has negative effects on the immune system so its inhibition is rather a good thing, if not negligible.

Methods

Now that the premise of this idea has been identified, there are two methods by which the proposed solution can work. The first one is a CRISPR knockout of the MCT1 gene in NK cells. Here is the proposed method by which this will occur:

1. A single-guide RNA will guide Cas9 to the MCT1 gene in the NK cell genome.
2. The enzyme will cut at the beginning and end of the gene, creating double-strand breaks, effectively removing the MCT1 gene from the NK cell.
3. NK cells will be cultured and expanded, with no expression of the MCT1 gene. To check this, flow cytometry can be done to assess if there is an expression of the transporter.

The second method is culturing NK cells with MCT1 inhibitors. These drugs are already in existence and examples include AZD3965 and AR-C155858. These small molecules inhibit MCT1 channels which effectively inhibit butyrate from entering the cell.

To test if this hypothesis is true, there can be several tests done to confirm the conclusions of this idea. The first step is to test if MCT1 knockout will lead to lowered butyrate levels in NK cells. This can be done using the following experiment:

1. Perform the CRISPR knockout in NK cells from NK92MI cell line and culture. Also, include a culture of wild-type NK cells as a control group for this experiment.
2. Culture NK92 cells in 1mM of butyrate for both groups.
3. Perform intracellular cytokine staining to analyze the cytokine levels of perforin and IFNγ in both groups. Furthermore, the levels of mTORC1 metabolism can be tested through pS6 intracellular flow cytometry staining. If metabolism and cytokine production are higher in the knockout-NK cells, it can be confirmed that the loss of the MCT1 transporter will inhibit butyrate from entering the NK cells.

Furthermore, testing is needed to confirm the effects these more effective NK cells would have against PDAC tumors. This could be tested in the following method:

1. Graft L3.6pl PDAC tumors into two groups of mice, one control group and one testing group.
2. Administer the same volume of NK cells to both groups of mice, one with wild-type NK cells and the other with the MCT1-knockout NK cells.
3. After one week, extract tumors from mice and measure their size. If the tumors of the MCT1-knockout mice are smaller than the wild-type mice, this strategy is more effective and viable against pancreatic cancer.

These methods will help design the NK cells and confirm their positive effect against PDAC.

Lines of Evidence

While the methods above certainly will concretely prove the proposed idea, it can be shown that there are multiple lines of evidence solidifying the foundations of the plan. Here are the counterarguments for why this may not work, and the evidence that disproves them:

1. MCT1 downregulation will not lead to lowered butyrate levels through some mechanism: The colonocytes of patients with inflammatory bowel disorder have been noted to have lower levels of MCT1 present on their surface. In one study, it was shown how this led to lowered butyrate oxidization for energy, pointing to how butyrate was inhibited from the cells when MCT1 was downregulated.
2. MCT1 knockout will lead to intracellular lactate buildup: MCT1 is also responsible for the transport of lactate. When this molecule builds up in NK and Cytotoxic T cells, it has been shown to greatly reduce their cytotoxicity. In one study, it was shown how inhibiting MCT1 didn’t lead to lactate buildup, as MCT4 was still available for transport. It was only when both of these transporters were inhibited that lactate started building up and the T cell cytotoxicity was reduced.
3. Butyrate is not the compound responsible for the microbiome’s effects on NK cells: In the first study discussed in this article, it was shown through qPCR analysis that IFNγ and perforin were greatly reduced in NK cells affected by the microbiome. In the study researching the effects that butyrate has on NK cells, both of these cytokines were reduced as well, showing a connection between the two.

While this strategy does not completely remove butyrate, it is significant enough to create an impact. Butyrate can be transported through simple diffusion through the cell membrane which would be incredibly difficult and possibly problematic to stop. Therefore, the best solution is just to inhibit MCT1 to limit the amount of butyrate being transported into the NK cell.

CAR-NK Combination Therapy

While inhibiting MCT1 is certainly a great way to boost NK cell cytotoxicity against PDAC, it could prove to be more effective to combine it with another promising treatment: CAR-NK therapy. This is where an artificial receptor that can detect tumor antigens is made to be expressed on an NK cell. The process behind this can be read about in-depth in this article.

Current studies are ongoing to fight PDAC using CAR-NK cells. One pipeline of interest is the targeting of mesothelin, an antigen expressed in PDAC tumor cells. Several antibodies have been developed which can target this antigen, including hYP218. Using the sequence of this antibody, a CAR can be designed from its variable heavy and light chains to create an scFv. Along with the transmembrane and intracellular domains, this will create a CAR that can detect mesothelin.

With this, the final therapeutic will consist of MCT1 knockout NK cells that express a mesothelin-targeting CAR. These cells can be administered to patients universally as NK cells do not have to be patient-specific like T cells.

Limitations

Despite strong evidence behind this treatment, there are still some limitations that have to be addressed.

One of these limitations is that we may not fully understand the role of MCT1, leading to potential adverse effects. In the evidence given, it is shown that with our current knowledge of the chemicals MCT1 transports, there should be little issue in performing a CRISPR knockout. However, this will change if we discover other chemicals which MCT1 may be responsible for.

Another limitation is that we cannot know for sure the full effects of butyrate on NK cells. Despite both cytokines IFNγ and perforin being affected, it is not known what other chemicals may play a role in the suppression of NK cells. For example, in the same study showing how butyrate limits NK cell effector function, it was shown another SCFA called propionate has similar effects to butyrate.

While these limitations certainly exist, the evidence suggested still gives a greater chance for a net benefit. However, they are still worth noting, and rigorous testing described in the methods section will be required for full trust in the therapeutic.

Discussion

In this article, the inhibition of MCT1 is reasoned to inhibit the uptake of butyrate in NK cells, leading to enhanced cytotoxicity and cytokine release. This can reverse the immunosuppressive properties of the microbiome in PDAC for increased tumor infiltration by NK cells. The inhibition of MCT1 can be facilitated by CRISPR knockout or the use of small molecules while NK cells are being cultured. Furthermore, the potency of the NK cells can be increased even more with the expression of a CAR targeting the mesothelin antigen expressed commonly on PDAC cells.

The microbiome is a complicated system that has coevolved with our bodies, introducing the opportunity for several mechanisms of homeostasis. For this reason, there must be careful consideration when attempting to manipulate this balance. In this idea, it is certainly a worthwhile endeavor considering how vastly the risks of PDAC outweigh those of interrupting the microbiome. To minimize this risk, however, even more extensive research is needed into how the microbiome functions.

While the effect it has on the immune system has only recently become a topic of interest, the microbiome’s influence on every system in the body is massive. Studying its characteristics is crucial to the development of effective therapies as shown in this idea. This also highlights how important it is to consider its effects on the therapy before starting human clinical trials, as overlooking a certain aspect of the microbiome could lead to unwanted complications. This is especially important when working with experimental therapeutics such as CRISPR-Cas9 and CAR therapy.

The future of biotechnology and cancer treatment is certainly looking bright with these treatments. While Watson, Crick, and Franklin gave us the structure of DNA in the 1950s, our knowledge of how it works and even manipulated it has opened a whole new field of research and treatments. While all of this is very exciting, it is also important to fully consider all possible outcomes of a therapy and its consequences. For example, the FDA recently launched an investigation into all CAR-T cell therapies because the T cells themselves were becoming cancerous in some patients. While the chance of this is still low and is greatly outweighed by the potential benefits, it is still a sign that new therapies still need to be sought after.

In conclusion, this idea has the potential to open a lot of doors in the treatment of PDAC, a cancer that has been feared for a long time. By incorporating the effects of the microbiome into consideration, inhibition of MCT1 can be used to inhibit butyrate, a chemical shown to have negative effects on the cytotoxicity of NK cells. This method can potentially increase the stark chances patients have against PDAC, hopefully increasing the quality of life for these people.

Sources

1. Zaiatz-Bittencourt, V., Jones, F., Tosetto, M., Scaife, C., Cagney, G., Jones, E., Doherty, G. A., & Ryan, E. J. (2023). Butyrate limits human natural killer cell effector function. Scientific reports, 13(1), 2715. https://doi.org/10.1038/s41598-023-29731-5
2. Yu, Q., Newsome, R. C., Beveridge, M., Hernandez, M. C., Gharaibeh, R. Z., Jobin, C., & Thomas, R. M. (2022). Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells. Gut microbes, 14(1), 2112881. https://doi.org/10.1080/19490976.2022.2112881
3. Peng, X., Chen, L., Jiao, Y., Wang, Y., Hao, Z., & Zhan, X. (2021). Application of natural killer cells in pancreatic cancer. Oncology letters, 22(3), 647. https://doi.org/10.3892/ol.2021.12908
4. Salvi, P. S., & Cowles, R. A. (2021). Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease. Cells, 10(7), 1775. https://doi.org/10.3390/cells10071775
5. Liu, X. F., Shao, J. H., Liao, Y. T., Wang, L. N., Jia, Y., Dong, P. J., Liu, Z. Z., He, D. D., Li, C., & Zhang, X. (2023). Regulation of short-chain fatty acids in the immune system. Frontiers in immunology, 14, 1186892. https://doi.org/10.3389/fimmu.2023.1186892
6. Sarantis, P., Koustas, E., Papadimitropoulou, A., Papavassiliou, A. G., & Karamouzis, M. V. (2020). Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World journal of gastrointestinal oncology, 12(2), 173–181. https://doi.org/10.4251/wjgo.v12.i2.173
7. https://healthcare.utah.edu/healthfeed/2019/03/why-pancreatic-cancer-so-deadly
8. Corbo, V., Tortora, G., & Scarpa, A. (2012). Molecular pathology of pancreatic cancer: from bench-to-bedside translation. Current drug targets, 13(6), 744–752. https://doi.org/10.2174/138945012800564103
9. Ghaneh, P., Costello, E., & Neoptolemos, J. P. (2007). Biology and management of pancreatic cancer. Gut, 56(8), 1134–1152. https://doi.org/10.1136/gut.2006.103333
10. https://cancer.ca/en/cancer-information/cancer-types/pancreatic/staging#:~:text=A%20common%20staging%20system%20for,can%20be%20removed%20with%20surger.
11. Rhim, A. D., & Stanger, B. Z. (2010). Molecular biology of pancreatic ductal adenocarcinoma progression: aberrant activation of developmental pathways. Progress in molecular biology and translational science, 97, 41–78. https://doi.org/10.1016/B978-0-12-385233-5.00002-7
12. Rivière, A., Selak, M., Lantin, D., Leroy, F., & De Vuyst, L. (2016). Bifidobacteria and Butyrate-Producing Colon Bacteria: Importance and Strategies for Their Stimulation in the Human Gut. Frontiers in microbiology, 7, 979. https://doi.org/10.3389/fmicb.2016.00979
13. Cong J. (2020). Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells. Frontiers in immunology, 11, 1989. https://doi.org/10.3389/fimmu.2020.01989
14. Liu, H., Wang, J., He, T., Becker, S., Zhang, G., Li, D., & Ma, X. (2018). Butyrate: A Double-Edged Sword for Health?. Advances in nutrition (Bethesda, Md.), 9(1), 21–29. https://doi.org/10.1093/advances/nmx009
15. Zhao, Z., Wu, M. S., Zou, C., Tang, Q., Lu, J., Liu, D., Wu, Y., Yin, J., Xie, X., Shen, J., Kang, T., & Wang, J. (2014). Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway. Cancer letters, 342(1), 150–158. https://doi.org/10.1016/j.canlet.2013.08.042
16. Thibault, R., De Coppet, P., Daly, K., Bourreille, A., Cuff, M., Bonnet, C., Mosnier, J. F., Galmiche, J. P., Shirazi-Beechey, S., & Segain, J. P. (2007). Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology, 133(6), 1916–1927. https://doi.org/10.1053/j.gastro.2007.08.041
17. Vijay, N., & Morris, M. E. (2014). Role of monocarboxylate transporters in drug delivery to the brain. Current pharmaceutical design, 20(10), 1487–1498. https://doi.org/10.2174/13816128113199990462
18. Liu, Y., Sun, X., Huo, C., Sun, C., & Zhu, J. (2019). Monocarboxylate Transporter 4 (MCT4) Overexpression Is Correlated with Poor Prognosis of Osteosarcoma. Medical science monitor : international medical journal of experimental and clinical research, 25, 4278–4284. https://doi.org/10.12659/MSM.912272
19. Jedlička, M., Feglarová, T., Janstová, L., Hortová-Kohoutková, M., & Frič, J. (2022). Lactate from the tumor microenvironment — A key obstacle in NK cell-based immunotherapies. Frontiers in immunology, 13, 932055. https://doi.org/10.3389/fimmu.2022.932055
20. Dornbierer, D. A., Boxler, M., Voegel, C. D., Stucky, B., Steuer, A. E., Binz, T. M., Baumgartner, M. R., Baur, D. M., Quednow, B. B., Kraemer, T., Seifritz, E., Landolt, H. P., & Bosch, O. G. (2019). Nocturnal Gamma-Hydroxybutyrate Reduces Cortisol-Awakening Response and Morning Kynurenine Pathway Metabolites in Healthy Volunteers. The international journal of neuropsychopharmacology, 22(10), 631–639. https://doi.org/10.1093/ijnp/pyz047
21. Lopez, E., Karattil, R., Nannini, F., Weng-Kit Cheung, G., Denzler, L., Galvez-Cancino, F., Quezada, S., & Pule, M. A. (2023). Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies. Journal for immunotherapy of cancer, 11(6), e006287. https://doi.org/10.1136/jitc-2022-006287
22. Gong, Y., Klein Wolterink, R. G. J., Wang, J., Bos, G. M. J., & Germeraad, W. T. V. (2021). Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. Journal of hematology & oncology, 14(1), 73. https://doi.org/10.1186/s13045-021-01083-5
23. Tomar, S., Zhang, J., Khanal, M., Hong, J., Venugopalan, A., Jiang, Q., Sengupta, M., Miettinen, M., Li, N., Pastan, I., Ho, M., & Hassan, R. (2022). Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors. Molecular cancer therapeutics, 21(7), 1195–1206. https://doi.org/10.1158/1535-7163.MCT-22-0073
24. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

Note from the Author

Thank you for reading my paper on this potential idea to help improve the treatment of PDAC. As a high school student, it has been amazing learning about all of these complex concepts that are usually reserved for university students. It’s here that I would like to take a moment to thank all of the researchers who make their work publicly available on databases for people like me to look at. It’s because of this that I was able to come up with this idea that has the potential to help many people.

It’s been super fun doing what a Ph.D. normally does, coming up with ideas and seeing if they correlate to their experiments (or in my case other researchers’ papers). My skills in critical thinking and writing have greatly increased as a result of this research and has prepared me on what to expect in an actual lab (other than the actual experiments).

Until my next idea comes, thank you for reading, and feel free to subscribe to my newsletter to see what I’m doing: https://divyanbavan.substack.com/ or send me an email: dbavan2@gmail.com