Some Thoughts on Immunotherapy of Solid Tumors

A) CAR CD28

The question is why CARs don’t infiltrate solid tumors & why they don’t proliferate as much when targeted against a solid tumor as they do when targeted against a leukemia or lymphoma. I think it could be because their CD28 doesn’t interact with cd80/86 so they become anergic. The story is that proteins from leukemias are presented by antigen presenting cells, but when cells in solid tumors die, their proteins are not processed by peripheral blood leukocytes (PBLs) but rather stay in the poorly vascularized tumor and are metabolized by other cancer cells.

If this is the problem, then there are well established approaches to overcoming it

1) Ablation. If there are multiple tumors then killing many cells in one (with x-rays or liquid nitrogen or whatever) is useful. This causes inflatimation and releases large amounts of tumor antigens attracting the attention of PBLs which then present the antigens

2) Vaccination. The targets of CARs are very well defined. If the CARs are not activated by tumors, they can be activated by inoculating with target antigens and adjuvant.

3) In vitro activation. The CARs can be activated in vitro before they are infused. The idea is to infuse memory CARs not resting CARs. An advantage of in vitro activation is that one doesn’t have to worry about damaging test tubes’ livers. It could be done with target antigen, IL15-IL15rAlpha, and anti CD-28 (maybe on beads or something because one better not infuse anti-CD28 into people).

I wonder how many groups are trying each of these approaches. I think it should be a large number.

B) Ordinary CD8 killers.

I know of three trials at the NCI each of which adds to anti PD1: Kevin Conlon adds anti-PD1, the Geraldine H. O'Sullivan Coyne, adds anti-CTLA4 and the Tim Gretens adds ablation and anti-CTLA4. I think some might get together and ablate and add IL15. They might also add an antibody such as anti-mesothelin.

There is also a much simpler way to redirect a TCR to a target – a bifunctional antibody with anti target and anti CD3. Amgen is trying this with the melanoma maturation antigen. I never got the logic of CARs – why does the modified TCR have to be a chimeric protein held together with amino bonds and not a CD£-anti-CD3 complex ? I do think that if one uses the anti-CD3 approach it is necessary to have activated CD8 killers, which can be obtained with any antigen especially including inoculation with non self HLA. Here the variable chains of the TCR don’t matter as the cells are targeted with anti CD3.

C) NK cells

There is a group trying trifunctional targeting antibody, anti FC III (also known as CD16) and IL-15 ClinicalTrials.gov Identifier: NCT03214666. I don’t see why just plain gamma globulin with Fc (which sticks to Fc III and Fc IV) and systemic IL-15 wouldn’t work as well. In any case, it seems to me that if one is causing NK cell proliferation and Fc IV expression with IL15, then one really wants a tumor specific monoclonal (again anti Mesothelin or maybe something new like the Hopkins (Vogelstein group) anti KRAS g12v presented with HLA A2 monoclonal.

Paul Ryan wouldn't recognize a free market if one bit him

Robert Costa and Mike DeBonis wrote an excellent retrospective on the career of Paul Ryan

‘He was the future of the party’: Ryan’s farewell triggers debate about his legacy

They are quite harsh, but not, I think, quite harsh enough.

My comment

This is an excellent article. Tough but fair with no sugar coating but also no discourtesy. However, there is one clear error. Costa and DeBonis wrote " to apply free-market principles to create opportunities in impoverished communities. The tax bill included a provision creating low-tax “opportunity zones,”"

Establishing opportunity zones might be good policy, but such zones are completely inconsistent with free market principles. The idea is to tilt the playinf field in order to favor the poor. The free market principle utterly rejected by advocates of opportunity zones is that the government shouldn't play favorites and should leave market incentives unaffected except as absolutely necessary to raise funds for necessary purposes.

Only someone unclear on the concept could think that the radical intervention in the economy with the aim of achieving higher welfare is based on free market principles, when it is clearly a rejection of free market principles.

Jack Kemp was a very decent man who genuinely wanted to help the poor. He also believed that he believed in free markets. But he wouldn't have recognized a free market if he tripped over it.

I think establishing opportunity zones is good policy. I do not think highly of free market principles. The fact that people who present themselves as advocates of the free market also propose non free market policies is just one reminder that free market principles can not solve our problems.

Now I think it is clear why Ryan and Kemp mistake social engineering for free markets. Opportunity zones would increase post tax profits and increase the budget deficit. They are consistently pro-business, if one considers the interests of businessmen to be only short term post tax profits and ignores any costs from the deficits the two of them created (with help from Roth, Reagan, McConnell and Trump but Ryan and Kemp are the men deficit lovers must love best).

The fact that Ryan was reputed to be more thoughtful than other Republicans demonstrates the utter idiocy of the party as a whole.

Again. I appreciate this excellent article.

Kidz theze dayz

I am quite confused. I see a racially integrated group of 4 long haired kids escorted by an (also young) scary looking police officer in riot gear.

Guess what banner they are bearing ?

The Wizard of Odds

Dorothy was in a strange land and had no idea what would happen next. The good witch of the North said she should follow the scientific method to a sound forecast. Unfortunately, neither she (nor anyone else) explained what exactly the scientific method is.

As she wandered down the yellow brick forking path of endless options, Dorothy was surprised by the voice of a heuristic firmly attached to a degenerate prior. She freed the heuristic from the prior and discovered that he was amazingly swift and flexible. She suggested that with his enormous speed he could quickly reach a sound conclusion.

The disconsolate heuristic sang that he could “If I only had a brain”

And they wandered off to find a shiny extremely strong hypothesis test with a razor sharp ax. The hypothesis test was rigidly chopping down the same deadwood. Dorothy said that his great destructive power could help him clear the way to the truth. All he needed to know was a promising direction, and he could eliminate all plausible but false hypotheses, leaving only the truth. The sorrowful hypothesis test explained that he had no idea how to create hypotheses or to decide which ones were worth testing and sang that he could find the truth “If I only had a heart”.

Having heard of the wonderful Wizard of Odds who could solve all of their problems, they made a bee-line for the land of Odds. On the way they stumbled over a cowardly line. The cowardly line said he made no claim about expected values or disturbance terms, because he claimed to be nothing other than what he was, the king of the summary statistics, the OLS regression.

They said that with his daring contempt for consistency and lack of any fear of bias, he surely cold provide them with a forecast. The lion explained that he could fit but didn’t forecast – that treating an OLS regression as a forecasting model might appeal to the foolish heuristic and might follow from implausible hypotheses which were easy to test and reject, but he couldn’t do it because he didn’t have the courage.

Finally they arrived at the City of Odds where they met a wonderful Wizard of Odds named Thomas Bayes who dramatically provided the probability of any conceivable event based on any conceivable data set. They were in awe until Toto barked. The Wizard boomed that they should pay no attention to the arbitrary prior behind the curtain.

Then Dorothy gave up on the effort to solve the problem of induction. And Toto too.

Anti anti Centrism

Charlie Pierce wrote a great post on the abuse of the word "centrist" as a term of abuse.

Then he criticized Bernie Sanders (whom I ask to sit out 2020 please). I am shocked to find myself almot to the left of someone who actually had a drink with Alexander Cockburn, but I think there is a lot to be said for demanding it all immeediately.

On "Centrist" you wrote [I comment]

Sanders here is being almost preternaturally optimistic [true] , to the point of being unacceptably [false*] glib [true] , about the difficulty of getting McConnell and the Republicans to do anything of the sort. [skip] that's a short route to chaos and a return to general minority status [very false **].

The fact is that there is a natural center in American politics [skip] It happens to be the solid place whence [false ***] can be launched real progress.

* it is irritatingly glib but that glibness is useful and not just to own the cons but also to appeal to the naive. I don't like Sanders's glibness. Nor did I like Reagan's, and I'm pretty sure that Kennedy would have gotten on my nerves in 1960 if I could have heard what he was saying (a uterus got in my way, plus I didn't know how to speak during most of his presidency). I am not the voter who matters. I always vote for Democrats (or Charles McMathias). The audience is those who sometimes vote, but only if beguiled by some preternatural optimism.

** Ask Sen McConnell how reliable sowing chaos is as a path to minority status. The Democrats are in opposition. The house passing popular measures (with 70% support) which are blocked by Republicans in the Senate is not their path to general minority status. The problem is something else ****

***"Whence" ? No Whither. Real progress is launched with slogans ("happy days are here again" was not a solid policy proposal) and dishonest promises (Obama didn't really think there could be health reform without a mandate (although the Republicans are proving that his 2008 bogus proposal actually works ... better than the old system anyway). Real progress lands in the solid center it is launched by those who have (or fake) preternatural optimism.

**** The real problem is that Democrats care about policy and are semi honest (case in point is H Clinton who lost to Trump, because she was perceived to be dishonest and, what's worse, is honest). The Democratic house would tie itself into knots trying to write a solid centrist Medicare for all Bill. "All" would be redefined to mean 90 % or 95%, and the party would tear itself apart fighting over which. The fools would actually pay for it with no aid from Rosy (the riviting) Scenario. There would be months of struggle with problem making "problem solvers".

Sending the Senate a bill declaring Medicare shall be available for all and this shall be financed by soaking the rich, would be deadly to Republicans. Trying to write a solid bill which could be implemented the second it was signed by Trump ?!? would be pure policy porn appealing only to nerds.

That's why Sanders is smart to talk about what others should do. Clinton would be scheduling meetings to discuss drafting a bill right now if Trump hadn't ended her effort to replace politics with solid policymaking.