Okay, I finally get Checkpoint inhibitors

Okay, I finally got Checkpoint inhibitors

After reading Ted’s summary about three times, I finally figured it out. I admit I never understood what a checkpoint inhibitor was before. Here’s how it goes (simple version):

When foreign or tumor cells arrives in the body, immune cells, especially T-Cells, multiply and go out and kill the foreign or tumor cells.

But it’s no good if the immune cells just keep multiplying because they’d clog everything up and cause a lot of problems. So the body has some molecules called CTLA4 and PD-1 that turn off the immune response when appropriate. We call these molecules checkpoints.

The T-Cells (immune cells) kill most cancer cells, but occasional cancers are successful because they happen on a way of using the body’s CTLA4 and PD-1 molecules (checkpoints) to suppress the T-Cells and stop the T-Cells from killing them, the cancers.

So drug companies have developed drugs that inhibit the checkpoint molecules (CTLA4 and PD-1) that are being used by the cancers to protect themselves from the T-Cells. And, natually, these are called checkpoint inhibitors.

And what’s IL-2?
It stands for interleukin-2 (brand name Proleukin). It’s a medication molecule that stimulates T-Cells like mad. But it has two problems: it’s quickly destroyed so it has to be given very frequently, and it goes all over the body and causes T-Cells to go wild throughout the body instead of just in the tumor, so it was incredibly toxic, and it never caught on.

And how would be NKTR-214 better?
If NKTR-214 is proven to do all it’s supposed to do, it will be prove to be delivered specifically to tumors, bind preferentially to cell types that fight tumors, and specifically activate them to start killing off the tumor cells. This means preferential activity and little or no toxicity.

I hope that this simplified version helps some of you understand this better. Figuring it out helped me! And a big, BIG, thanks to Ted, for explaining it so I could finally understand it.




That’s about it Saul! I wish I could write that concisely.

There are two other concepts that I hope people will also walk away with. The first is to make sure that you understand the “push-and-pull” strategy of combining therapeutics. There is competition heating up to take the existing “pull” therapies, like CTLA4, PD-1 and PD-L1, then combining it with “push” therapies, like NKTR-214.

The second concept is that there are several “push” therapies. In addition to Proleukin and NKTR-214, there are the TLR7 agonists, like NKTR-262. The main difference between NKTR-214 and NKTR-262 is that -214 is just one type of growth factor, and -262 can turn on many growth factors. Going back to the sugar and kids analogy, -214 is like going to a candy store, and they are giving away jawbreakers for free. That promotion will attract a lot of kids. However, -262 is like the store is giving away all the candy, and that will cause a frenzy.

For “push” therapies, there is a whole gamut of molecules we can use and companies are trying to find out what is the optimal combination of “push-and-pull.” The main problem here is that the more we amplify the immune response, the closer we get to that edge between efficacy and tolerability.

So the question is, which will be effective? It could be -214 adds just the right amount of “push” and doesn’t send it over the edge to toxicity. Or it could be that -214 is not enough, and we need to give an extra “push,” like the TLR7 agonists or something different. I think that answer will come out as the story unfolds over the next 10 years or so.

Best wishes,



Hey Ted:

As regards these therapies, there is perhaps an unintended assumption implicit in the analysis that assumes that everyone and every cancer should respond in kind.

The history seems to be that this is not the case…same tumor in different patients respond differently…even biomarkers discovered that predict responses to IL-2.

On top of that would be the considerations of resistance and tumor adaptations to immunotherapies.

Why should an investor assume these won’t become important clinical implications for response rates and thus NKTR may not get us to the top of the mountain after all?

$16 bilion market surely has some serious assumptions priced in already…but give us your worst bear case if you would.

Disclosure: not an investor in NKTR with no immediate plans to do so but for whom I can always change my mind as valuation and circumstances change.


Hi dumaflotchie

You’re asking some really good questions that have perplexed scientists and clinicians ever since we’ve started developing drugs! These are entire fields of study onto themselves. The first is disease heterogeneity, that is, in the same broad categorization of disease, when we look from individual to individual, the disease process is not the same in everyone.

This concept is applicable to every disease that we are trying to treat. A good example is Rheumatoid Arthritis. Here we have multiple therapies that target different pathways of the disease, like the anti-TNFs, Xeljianz, Actemra, Rituxan and Abatacept. Yet there always seems to be percentage of the patients that are intractable to treatment, and we don’t really understand why.

The same thing can be said about cancer cells. In many types of cancer, there will be patients who can be cured, disease stabilized or no effect. And here is something even more puzzling. In mouse models, we can take the exact same tumor cells, implant them into 10 mice that are genetically identical, and treat them with our drug. Despite everything being identical, the responses will vary among the group, with cures, impaired tumor growth and no effect! Why is that, and how can we ever hope that we will find a single treatment that is effective for 100% of a patient population.

There may be hope for some types of tumors, given the advances of genomics and data analysis techniques. The ability to characterize the cancers from different individuals on a genetic level has made it possible to predict which patients may respond to treatments. For example, there has been some great advances in using biomarkers to stratify breast cancer patients who we believe will respond to therapies like Herceptin. If we could prequalify patients to those that will be responsive to treatment, that should increase the response rates dramatically.

For the tumors that develop resistance to therapies, this is a very real phenomena and concern. It really is a numbers game, where it’s like an arms race between the immune system and the cancer cells. The cancer cells have the ability to multiply and try out different mutations. So if the cancer cells can persist the onslaught of the immune system, there is always a possibility that they will develop some strange “cloaking” technology that will allow them to evade the immune response.

I’m not enough of an expert in the clinical side of the biz to make an accurate bear case scenario. I’m more of a Discovery side scientist, but after 15 years in the biz, I’ve managed to stay awake during enough of these clinical talks to be able to make some sense of what they are trying to do. Heck, I’m not even an oncologist — I just have the benefit of working with those guys a lot in my job.

But I’ll give it a shot! There is a rule of thumb that about 30% of the population will be unresponsive to a best of class treatment in any disease, for whatever existing evasion mechanism that they have already in place. So using that same rule of thumb I would say that of the 70% that would respond, maybe 30% of those might relapse due to development of some evasion mechanism. So in a best case scenario, if this combo of Opdivo and -214 is best-in-class, we might be looking at 50% of the patients will be treatable.

That conclusion is certainly up for debate!!!

Best wishes,



Great way to sum it up!
I am a clinical pharmacist and have been trying to get this strait, and come up with a way to clearly summarize it. After several attempts at a “brief” summary - I just could not get it down to a brief, clear, concise write-up.

I appreciate it, as it helps how I think about it, and how I can explain to others.

Thanks again!


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Apologies for posting essentially the exact same thing as I posted in another thread, but I had intended to post within this particular Checkpoint inhibitors thread as I heard about the new Nobel Prize announcement earlier this am. Here is a link for quick reference to the post from CMFTedyun that prompted Saul to start this thread in the first place back on March 25, 2018.

I just heard on NPR this morning that a Nobel prize was being jointly awarded to 2 different scientists for their work on checkpoint inhibitors as a cancer treatment, which immediately brought to mind the prior discussions of Nektar on this board.

Here are some links with some info about the Nobel Prize announcement, which is tangentially relevant to Nektar Therapeutics.






no present NKTR position…the timing of this report seems quite ironic (to me) in light of this Nobel announcement
Tempted to re-consider adding a NKTR position, especially since my wash sale period has passed as of a week or so ago from the last position
Guessing that today being the first day of a new month/quarter may have been part of why the award was announced today