The Swiss Army knife: How Many Things Can You Treat?

There are a few things in the world that truly have a lot of utility. The above mentioned Swiss army knife. My 1998 Taco, may she rest in peace. A frying pan. Metformin. Pembrolizumab. It is this last one, pembrolizumab (PB from now on) that I want to look at today. As I started off in healthcare, one of my jobs was to get a health history on patients and take down all the medications they were using. Even without any formal education and not having any experience, certain medications started to stand out. Statins, metformin, baby aspirin, metoprolol, and others. Keytruda is one that I remember seeing not infrequently, but always in folks with a history of some sort of cancer. Being a little bit more educated now days, I know that Keytruda, the brand name for PB, is quite a jack of all (cancer) trades. 

A look at the lists of FDA and off label indications for PB is pretty impressive. PB is FDA approved for certain types of melanoma, NSCLS, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma, Hodgkin's lymphoma, primary mediastinal large b-cell lymphoma, microsatellite instability high cancers, gastric cancer, cervical cancer, liver cancer, Merkel cell carcinoma, SCLC, and probably more that I missed. Other non FDA uses are esophageal, nasopharyngeal, colorectal, breast, and prostate cancers along with mesothelioma. Whew, thats a list for you. So why is PB so useful for all of these cancers? 

Programmed death receptor 1 or PD-1, also the name of my new oncology themed thrash metal supergroup, is a 'checkpoint' that functions to keep the immune system from self harm. Without PD-1, mice have been shown to develop lupus like syndromes. The expression of PD-1 is likened to the blood on the doorframe causing the angel of death (in this case the immune system) to pass by. The expression reduces the function of T-cells to kill the cells who are doing the expressing. In cancers that have greater PD-1 expression, the immune system is less effective in attacking, PB blocks PD-1 allowing the immune system to again start to attack the cancer cells. 

Cancers can be tested for this expression and based on that, drugs targeted at that mechanism of cancer-defense can be used. Like the right tool for the right job. There are myriad other targets that could be discussed but let's stay with PD-1 for a while. 

So PB binds to this PD-1 on lymphocytes, and normally, the PD-1 would bind to PD-L1 or PD-L2 (L is for ligand) and deactivate the lymphocyte. When a cancer has these PD-Lx doodads, then the lymphocyte thinks "oh this is just Larry, he isn't a threat" and doesn't do anything more. But now, the lymphocyte has PB blocking that connection, so it sees Frank, not Larry like it did before. No one likes Frank. Maybe PB is like giving the lymphocyte glasses to allow it to see the real target? Whatever, just know that blocking that is good for fighting cancer cells. 

There is some evidence that PB is still effective in tumors that lack PD-L1 expression which is interesting. Could this be because it has a sort of prophylactic effect on the tumors? Preventing the new expression of PD-L1 and thereby allowing the immune system to do its job for longer during the cancer's course. A study in Frontiers in Thoracic Oncology, showed something similar with other PD-1 inhibiting monoclonal antibodies similar to PB. The differences in response rate for PD-L1 positive versus negative is pretty stark however, it seems as if certain chemotherapies promote PD-L1 expression during treatment, so PD-1 blockers become more effective. Not to mention that inflammatory signals and mutations in the tumor and its environment make PD-L1 expression more likely. So the longer it goes on, the greater chance it starts to wear the PD-L1 jersey. 

In difficult to treat cancers, would it be worth finding a way to promote PD-L1 as a tumor defense mechanism just so we could use these drugs? Is there a trade off when a tumor develops that mutation that it loses another factor? Or is it just the fact that these tumors have PD-1 that when it is taken away, they respond normally, not that PD-1 makes the tumor more aggressive? I don't think that made sense. Does PD-1/L1 make a bigger, badder cancer even if you block it? Or is the PD-1/L1 compensating for something else? Just spitballing here, probably adding PD-1/L1 would take away the effectiveness of other cancer drugs so it would not be worth it. Anyways. 

All this to talk up PB but one cannot forget the adverse reactions and side effects. Many immune-mediated conditions may arise, which makes sense since PB jacks with the immune response. Others include cough, weight loss, rash, arthralgia, flu-like illness, hypo or hyperthyroidism, and anemia among others. 

That is my story and I am sticking to it. No ifs, ands, or buts about it. I hope that made some sense at some point. I hope everyone is enjoying their summers and staying safe out there. It is the Street Machine Nationals at the fairgrounds this weekend so that is where I will be, just follow the deafening bellow of the afore mentioned street machines. Love y'all, bye. 

References

Beyond PD-L1 Markers for Lung Cancer Immunotherapy by Rojas-Krawczyk et al., in the International Journal of Molecular Sciences 2019

First-Line Treatment Options for PD-L1–Negative Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis by Peng et al., from Frontiers in Thoracic Oncology 2021

Image from the KEYTUDA website (no connection to me whatsoever ever I just like the image)

Is PD-L1 a consistent biomarker for anti-PD-1 therapy? The model of balstilimab in a virally-driven tumor by Grossman et al., in Oncogene from 2021

Pembrolizumab from the NIH StatPearls

Pembro Plus Platinum-Based Chemotherapy Improves Survival in Advanced Pleural Mesothelioma by Storrs in ASCO Daily News 2023

What does PD-L1 positive or negative mean? by Ribas and Hu-Lieskovan in the Journal of Experimental Medicine 2016