ASH 2018 unposted posts

  1. Science and the real world: Too many abstracts touted their “real-world” data meaning to say their analysis was retrospective. No shame in a well-done chart review, but calling it “the real world” dilutes the phrase. When the NCI director referred to real world data in his not-well-enough-attended ASH speech, it was to describe prospective collection of structured data in routine clinical practice. It can also be used to describe pragmatic clinical trials, with looser eligibility criteria and fewer treatment restrictions. The “real world” abstracts I saw were neither.
  2. Steve Horwitz’s weird weekend: How many oral abstracts can one person have in a single meeting? Apparently, four; three of which were spread over two T-cell lymphoma sessions held on the same day. These were all multi-center trials, one global, so not exactly venues where one may cede the podium to their mentee (some of whom had their own orals to deal with). But sheesh.
  3. T-cell lymphomas have their day (maybe?): The global trial was ECHELON-2, and it showed an overall survival benefit of first-line brentuximab vedotin + CHP over CHOP in CD30+ T-cell lymphoma. Which is great, only ~80% of patients in the control arm did not get BV on progression due to the trial being global and BV not being available in most of the countries. There were several more would-be flies in the ointment, but US FDA approved BV for first-line treatment of CD30+ TCL even before the paper was out in The Lancet (which was on the day of the talk). Thus the incredible path of data for BV in first-line TCL was: press release -> FDA approval -> Lancet paper -> ASH oral. Again, sheesh.
  4. Spotlight so bright: I moderated an oral abstract session, and it was fun, but oh wow did the spotlights hurt my eyes. Much respect for anyone who has to stand in front of them professionally.
  5. Let’s have it in San Diego every year, please, and thank you.
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The three flavors of interleukin-15

One thing I realized at SITC this year was that not many people know (or care?) about the difference between the IL-15s now being tested in trials. There are: the recombinant human (rh)IL-15, the IL-15/IL-15Ralpha heterodimer (hetIL-15), and ALT-803, the “super-agonist”. You’re better of reading a more comprehensive review, but some highlights are below.

  • The simplest, oldest, and seemingly most potent is the plain vanilla rhIL-15.
  • Four dosing strategies have so far been tested: bolus (too toxic, published), subcutaneous (OK, about as good as ALT-803 in increasing NKs and CD8+ T cells, also published), 10-day continuous infusion (the most potent, but who wants to sit in a hospital for 10 days, should be published soon), and a 5-day infusion (same 40-fold increase in NK numbers in half the time! presented at SITC)
  • None of the patients in any of the regimens had a RECIST response, but most mounted an impressive lymphocytosis, leading to several planned combination trials
  • It is available for investigator-initiated studies through CTEP. They will also give a few vials for preclinical studies.

  • Novartis owns hetIL-15, and is running the phase I alone and in combination with their anti-PD-1. Nothing published, but I’ll have more to say about it next year.

  • ALT-803 is an IL-15/IL-15Ralpha heterodimer blessed with a single point mutation which confers upon it both increased binding to the common gamma chain, and validity to the claim of new IP.

  • It is the only one shown to have efficacy as a single agent (though not in solid tumors), and the only one to be part of a published and/or presented combination (with nivolumab in NSCLC, and with rituximab in FL).
  • What’s presented so far makes it less potent than rhIL-15 in increasing cell counts, but more convenient to give: via once-weekly subcutaneous injections for an 8-fold increase in NKs.
  • The company, Altor Biosciences, had been fairly open to IITs — one of them is currently open at NCI’s GU Malignancies Branch — but maybe not so much since being acquired in August 2018 by NantCell, a Patrick Soon-Shiong company.

There’s more, of course, but I’ll end instead with another plug for our review of cytokines in cancer therapy.

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Yes, CAR-NK cells are exciting (as exciting as they can get after a phase I single-center yet-to-be-published trial)

For more than a year now, the big names of CAR-T-cell world have been sharing their excitement about the potential of NK cells to be a much better CAR carrier. There are many hypotheses about why that would be, but you can hypothesize all you want until you give the product to humans. PET scans can lie, but not nearly as much as your average transgenic mouse model.

Well, anti-CD19CAR-NKs have now been given to at least 9 humans, as reported by Dr. Katy Rezvani from the MD Anderson Cancer Center at the SITC Annual Meeting a few days ago, and what she reported was as good as it gets for a first-in-human trial of a new gene/cellular therapy. The five takeaways:

  1. Off-the-shelf cord blood-derived NK cells carrying a CAR can safely be given to humans without HLA-matching. This could decrease both cost and time to treatment.
  2. None of the nine patients had cytokine release syndrome or neurotoxicity. After all, NK cells aren’t big cytokine producers.
  3. Six of nine patients had a complete response and one more had a partial response for a 77% response rate.
  4. One of those CRs and one PR were patients with CLL and Richter’s transformation, another CR was in a 70-year-old with double-hit lymphoma, and yet another in a patient with CLL and 17p deletion. These are tough diseases.
  5. Contrary to what was hypothesized about NK cell longevity, the CAR-NKs persisted for up to six months after treatment. We still don’t know what that means for CAR-Ts, let alone CAR-NKs, but I consider it a win each time experiment refutes theory.

So yes, I am also excited about CAR-NKs. However:

  1. This is an unpublished, non-peer-reviewed, single-center experience. There could be research hospitals out there giving CAR-NKs with results too horrible, or just too middle-of-the-road, for early promotion.
  2. CLL is notoriously difficult to stage, and five of the nine patients had CLL. Consider the MURANO trial (Venetclax-Rituximab combo fo relapsed/refractory CLL), in which the investigator-assessed complete response rate of 26.8% turned to 8.2% on independent review committee assessment.
  3. Follow-up is limited and it is too early to know the response duration. Long enough to get to an allo transplant, at least?
  4. The same limitations in target availability we have in CAR-T cells apply to CAR-NKs. It has to be a surface antigen with limited to no expression on normal cells. There aren’t too many of those, particularly in solid tumors.

Still, kudos to Drs. Rezvani, Shpall, and others at MD Anderson. This is as good as it gets at this early stage.

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What I believe that most people probably don’t (no data behind this, just the armchair)

The world in general, and the US in particular, is spending too much on goal-directed, targeted biomedical research while undervaluing both applied and theoretical physics. Picture Leonardo da Vinci drawing helicopters: that’s the modern-day cancer researcher. The universal cure for cancer — and there should be one, if humanity survives long enough to create it — will not come from an NIH grant. If grants are involved at all, it will be something initially funded by the National Science Foundation. The current system of funding (government, non-profit, biotech, you name it) is broken, and if you account for the opportunity cost it is a complete disaster. Each of these statements deserves at least a paragraph, but I am saving my carpal tunnels for a manuscript, an LOI, and a couple of protocols (oh, the irony).

In the meantime, a few things physician-scientists should do for the overall good:

  • find causes and create better prevention strategies, because a look at the SEER database will tell you that it’s not just bad luck;
  • eliminate barriers for administration of known curative therapies world-wide (do we really want to leave this to politicians and economists?);
  • ensure rapid and honest evaluation of the many new treatments, procedures, and diagnostic/prognostic methods coming out of the biomedical behemoth.

How beneficial any of this would be for one’s career is a different question altogether, but let’s not get into incentives because RSI. I am also very open to opposing opinions, since my being wrong would make my life easier.

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Brush up on your Serbian

Serbia’s public broadcaster, RTS (that’s PTC in cyrillic) has a good chunk of its archive spread across multiple YouTube channels, and it is magnificent (this one in particular).

Observe the 1960s-1990s televised plays and TV dramas. I still have vivid memories of watching one particular product the first time it aired, about a Serbian family keeping in touch with their ex-pat relatives in Germany via VHS tapes. Replace camcorders with smart phones and speed up the timeline to account for the internet, and it could have been shot today. Technology changes, people don’t.

My favorite childhood TV show hasn’t aged well at all; then again has anything from the ‘90s? If you consider most of it was made during a civil war and in a time of hyperinflation it is actually quite good. What was 90210’s excuse? Better kids’ shows have been made in Serbia both before and after.

Best for last: the celebration of hard core nerddom that is Serbia’s longest-running quiz show, important enough to have its own channel. It starts with anagrams and math problems, makes a detour to Mastermind, then finishes off with three different ways to test for trivia. Jokes about the autism spectrum would be writing themselves if this were an American show, but it’s not, and (before I left, at least) Serbian viewers still had some admiration for the participants. It is all very serious and competitive, and has been on the air every weekday for the last 24 years. (A political side-note: this does not mean Serbia is free from anti-intellectualism, quite the opposite in fact. Some combination of militant anti-intellectuals, gas-lighters, and proponents of economic/financial scientism has been in positions of power since the early 90s. There are no lessons here, just observations).

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A few unpopular (in certain circles) opinions from a person who has no rights having them

For better or worse, the American system of government is strong. Those who say otherwise have a financial interest in people thinking the opposite.

Culturally, US has more similarities with Iran than with Saudi Arabia, even if you count religion and religiosity as part of culture. The Christian right is working hard to make them even more similar.

Though still quite hard, it’s easier for a high-skilled immigrant to come to America than to any other country in the world. Comparison is even more favorable for low-skilled and unskilled immigrants. For all of them, quality of life, acceptance, and protection they get are better than anywhere else.

The randomness of the Green Card lottery process is a feature not a bug.

Reading the non-fiction sections of The New Yorker, The Atlantic, and whatever their conservative equivalents are, is good for generating fake insight but ultimately pointless. The Economist is useful for a tiny segment of the population but lets be real: if you’re reading this you are not it.

The only useful section in the daily newspapers is Local. Maybe Sports, if you are into that sort of thing, but professional and college sports are a scam so stick with the amateur leagues.

TSA agents and airline personnel are nice people but some passengers check out their brains at the curb and make everyone’s lives less pleasant.

Apple hardware products are underpriced for what you get but do you actually need what they offer? This doesn’t include the AirPods, which are the best thing Apple has made in the last 20 years and still underpriced; though they unfortunately resemble in both name and appearance a mind control method from Doctor Who S2 and paired with a smart phone are not far from it.

The world doesn’t need another IPA. America needs more tripels.

This is all coming from a non-immigrant resident alien with no expertise in politics, international law, transportation, or technology. I do know beer though.

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Voices in my head, 2018 edition

(voices as in podcasts, not a psychotic episodes)

  • Conversations with Tyler: I much prefer this over his mostly spartan, often cryptic, and always clueless about things medical blog Marginal revolution. Cowen‘s interview style brings out the best from people; it is also a good and rare example of clear thinking. Compare and contrast his chat with Malcolm Gladwell and Patrick Collison’s chat with Cowen: when answering, Gladwell uhms and ahhs and changes direction mid-sentence; Cowen pauses for a half-second, then produces paragraphs of prose that could have been lifted right out of an encyclopedia. Not to belittle Gladwell — for one, I’d be even worse (as anyone who had to finish my sentences for me can confirm); and two, he is responsible for
  • Revisionist history: He had me at Food Fight. Gladwell embraces and owns his Well, actually kind of story-telling — even the show’s name is a big Well, actually to the Gladwell-haters. And good for him, because the stories are marvelous in both topic and style, and make me want to read his books again.
  • Sources and methods: Two ex-spies talk about learning and cognition. They are still in intelligence-gathering mode, interviewing guests you‘re unlikely to hear anywhere else. It’s how I learned about Tinderbox (and you can too).
  • America the bilingual: One part pep-talk to encourage the pre-1990s waves of immigrants to America to take up a second language, one part advice to parents raising multilingual children. The latter validated my plan to ~~save money~~ strengthen the offspring’s Serbian by shipping them across the Atlantic to spend some quality time with the grandparents.
  • Novel targets: Finishing of the list of men talking to each other is the best oncology podcast I’ve come across. It may be heavily slanted towards immunotherapy, and not zealous enough in dampening the hype, but it tries.
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The culture that is Nortwest Washington DC

I have cut my commute down to 40 minutes door-door (from ~2 hours), 25 of which are walking, and we only have to pay 1.69 times the rent. Yay?

Some observations about our new neighborhood from a Serbian/European/Baltimorean transplant.

Dogs are everywhere.

Runners and cyclists too.

And a couple of homeless people. One seems to have staked out a bench I pass by every day.

Very few children. Assuming all the little Audreys and Maddisons are attending their ballet lessons, or whatnot.

Restaurants with street seating. It’s like I’m back in Belgrade. Alas, most of them serve nothing but greasy American classics, only they call it Southern-style and put even more grease.

Are people who eat at these places the same ones doing all the running?

Why do two different streets in the same neighborhood have the exact same name? If you put a super-block that cuts a road in half, does it not make sense to rename one of them?

Safeway is a dump.

The title may remind you of Marginal revolution. That’s on purpose. Go read it.

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→ Annals of internal medicine: Curiosity

Old (1999), but still good.

When I was a house officer and installing one of the first right-heart catheters, the machine that showed intrapulmonic arterial pressures was enormous and was equipped with strain gauges rather than computer chips. Making it work was difficult. After the line was in, the attending, the nurse, and I tried desperately to adjust the machine to show the pulmonary arterial pressure waves. We could not get them. The line on the screen remained flat. We manipulated toggle switches and strain gauges for about 15 minutes. Nothing. Finally, I glanced at the patient: He was dead.

The story that follows is even better.

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