Reactions to cancer immunotherapy book _The Breakthrough_ by Charles Graeber

1. Cancer immunology or immunology more generally may be relatively crowded fields for me to enter as a biology researcher; however, there might be other reasons to enter anyway.

“As of June 2018, there were reported to be some 940 new immuno-oncological drugs being tested for breakthrough designation and FDA approval. Another 1,064 new immunotherapy drugs are in the labs in preclinical phase. That’s 2,004 new cancer drugs in just a few short years. This speed of change is highly unusual in medicine, and totally unprecedented in cancer. And by the time you read this, those numbers and the science behind them will have advanced again.”

“There are now reportedly 164 PD-1 / PD-L1 drugs in the pipeline between preclinical testing and consumer marketing, and industry insiders suspect there may be many more being developed in China.”

“The result is billions of dollars and scores of talented specialists now devoted to cancer immunotherapy. The funding torchbearers of the field such the Cancer Research Institute, started more than seventy years ago by William Coley’s daughter, have been joined by new organizational infrastructures to support that work, among them the Biden “moon shot” Cancer Initiative, to rethink medicine as a whole, and cancer most specifically; the Parker Institute for Cancer Immunotherapy to fund and coordinate researchers and clinical trials as never before; public appeal drives such as Stand Up to Cancer; (SU2C), which directs hundreds of millions of donated dollars directly into research and clinical trials; and a gold rush for commercial pharmaceutical companies and startups and the dozens of biotech venture capitalists that fund them. Several researchers have quipped that there are now two types of drug companies: those that are deep into cancer immunotherapy, and those that want to be.”

There are many caveats with my claim. Perhaps there is a ton of work left to be done to make immunotherapy promising, and immunotherapy is that good of a tool to have against cancer or pandemics. Maybe a bunch of money and industry interest are incoming, but there is still a bottleneck in innovative research. In computational research specifically? Is there a bottleneck in research talent in either (e.g. maybe there aren’t many people who have been trained in certain skills or types of research in cancer immunotherapy or immunology)? And, as always, beware statistics. However, I do tend to think that, with so much funding and hype around the field, there’s bound to be some incoming research talent, including computational talent. I would be willing to bet on myself as being able to advance immunology or cancer immunotherapy, at least marginally, but I’d also bet that I could advance other fields by more. However, for my PhD research choice, this may be outweighed by factors by aiming to be in a top lab or being in a field that is (currently) prestigious and reliably funded.

I am now more interested in immunology that engineers the immune system. See Preface below for my mixed feelings about the promise of this approach vs. say broad-spectrum antimicrobials. I guess that means understanding how it works, but in a focused way. I think you should argue as a prior that it’s hard to predict where the next finding from immunology will come from and it won’t necessarily follow the past, but if the past is some indication, I do think that empirical work, including the flavor of work of Allison and hx, is more robust. As opposed to “epistemic base” flavor stuff, specifically molecular-level speculative biology. Also, note that you might want to engineer the immune system to go stronger or weaker (again, how do the pathogeneses work?).

2. Cancer immunotherapy is currently very expensive. (This might be worth trying to solve.)

As of 2018, “[p]ricing for Yervoy—the trade name for the anti-CLTA-4 drug ipilimumab—is typical, costing more than $120,000 for a four-course treatment. Merck’s anti-PD-1 drug Keytruda, for advanced melanoma, costs $150,000 for a yearlong treatment.”

3. Cancer is potentially not as much a death sentence as I imagined.

“Until very recently we’ve had three main methods for treating cancer… These ‘cut, burn, and poison [surgery, radiation and chemotherapy]’ techniques are currently estimated to be able to cure cancer in about half of the people who develop the disease.” However, Graeber doesn’t provide much backing for this estimate. Is it true? I feel some doubt. The word “cure” seems strong; a cross-check with https://slatestarcodex.com/2018/08/01/cancer-progress-much-more-than-you-wanted-to-know/ suggests ~50-70% as a 5-year survival rate across cancers (the percentage of people who survive five years after being diagnosed with cancer), which is less than a cure but still pretty good. Maybe a majority of those 5-year survivors were actually cured and never experienced a remission. It’s unclear.

4. Maybe consider or ask about cancer immunotherapy, on its own or in combination with other therapies, if you or someone you know gets cancer (I’m not a doctor).

“[Ipi] was an immediate game changer, reducing deaths from late-stage melanoma by 28 to 38 percent. The first phase 1 clinical trials started in 2001, long ago enough to qualify 20 to 25 percent of those patients with “long-term survival” benefit. That’s still less than half of the patients, but a great deal better than the low single-digit survivor percentages only the year before.”

“There are now at least half a dozen approved anti-PD-1 / PD-L1 drugs… The anti-PD-1 / PD-L1 drugs seem to work best if a patient’s tumor is expressing PD-L1. For that subset of patients, the drug has worked well, providing durable and sometimes complete responses.”

This section will become out of date as new trials come out. I can only speculate on whether immunotherapy will offer improvements for other cancers in the coming years.

5. One might imagine cancer as analogous to viral infection; both involve potentially hijacked cells creating many other hijacked cells (cancer by outgrowing normal cells, virally infected cells by spreading viral particles). I should read about how both of these cause diseases and their pathogenesis. Without knowing anything, I can imagine that they cause disease by (a) creating big masses in your body through uncontrollable replication and/or (b) decreasing your normally functioning cells via infection and/or outcompetition.

6. I have a bias against engineering the immune system instead of letting it perform naturally unless it’s an emergency and the alternative is clearly worse; this bias is confirmed by this book. Two notable emergencies:

  • You’re clearly going to die of cancer without treatment (the book’s subject).
  • It’s a deadly pandemic (e.g. case fatality rate > 25%) where traditional vaccine approaches don’t work, so you should try some of the less tested approaches to immunotherapy that have been tried in cancer. Approaches mentioned in the book include
    • vaccines or live infection
    • passive immunization via transfusion of serum/blood, antibodies or T cells
      • adoptive T cell therapy (a cellular therapy, i.e. drug is a cell)
    • checkpoint inhibitors (T cell-specific)
    • broad stimulants of the immune system or parts of it (e.g. interferon, IL-2 or TCGF for T cells)
    • CAR-T cells
    • bispecific antibodies to chain T cells with cancer or infected cells
    • ways to make cancer or infected cells express unique antigen to be visible to the immune system
    • 50+ targets in the tumor microenvironment
    • oncolytic virus therapy
    • combinations of such with existing therapies and each other
    • more?
    • You could consider these in combination with the suite of antimicrobials as the tools in our arsenal in a pandemic:
      • antibiotics
      • antivirals (e.g. ART)

7. I learned various things related to

  • the standards needed in experiments to prove various findings in cancer immunotherapy
  • the strategies for discovery of such findings
  • the stories behind key concepts in immunology
  • various wet lab techniques
  • pictures of certain phenomena

These may be expanded and may be of interest to fellow scientists.

8. Below, I outlined my favorite parts of the book as it fits my background and interests. This may be helpful to those only interested in specific questions or sections, as well as those who have read the book and wish to have a mental map of its contents. I think those interested in the bioscience and clinical aspects (e.g. point 7) will enjoy reading the book in full. I think others will benefit from just a summary, which can be found in Appendix B of the book.

  • Preface. Argues that, to treat cancer, it is better to use the immune system than to use a typical drug, because the immune system adapts against cancer’s mutation, unlike a typical drug. Even though this is true, isn’t it possible that the immune system is already doing what it can to fight a disease, so there may be little to gain my engineering/optimizing it further? I agree that there’s a clear optimization for immunocompromised people (get them off immunosuppressants or fight their HIV/AIDS) but otherwise it’s not obvious to me that just because the immune system is strong and adaptive, that we should be looking to further engineer it to do better.
  • Introduction
  • Chapter 1 Patient 101006 JDS
  • Chapter 2 A Simple Idea
  • Chapter 3 Glimmers in the Darkness. How we know how the immune system works (“In retrospect… horrible, glaring exception”). People seeing immune system not working against cancer as proof of its non-relation. Some Rosenberg and cancer immunologists’ stuff in 1970s-1990s (Coley repeat but with serum/blood transfusion instead of infection, then a more specific transfusion of T cells created by pig in response to tumor, then IL2-fertilized T cells plus IL2 (accidentally discovered in 1976 as fertilizing healthy T cells in an attempt to grow leukemia, more appropriately T-cell growth factor for crazy T cell growth numbers, produced beyond scarcity with rDNA spurred by interferon, the 1957-discovered “interfering” hormone) <1/2 helpful study followed by news and FDA approval but difficulty in reproducing and more scientists avoiding immuno for cancer area) (“In 1968… the most successful would be the ones who weren’t even trying.”) So Rosenberg and previous era can be thought of as a. IL2, b. maybe cancer vaccine (mash up tumor), c. serum and/or T cell transfusion [b. and c. having analogs for infectious disease, a. is a new idea that didn’t pan out so well, vs. these checkpoint inhibitors which may pan out reasonably well].
  • Chapter 4 Eureka, Texas. Jim Allison. How do T cells recognize and get activated at all? Find TCR, then CD28, then co-inhibitor CTLA-4.
  • Chapter 5 The Three E’s. This is basically immuno again but maybe post-Allison and the author trying to go back and forth and/or put things chronologically, I’m not sure what the logic of the order is (1974 Stutman nude (non-immune) vs. normal mice getting carcinogen and same tumor rate; 1988 Schreiber and Old TNF and IFNy knockdowns (genetic mutation, antibody) stop immune response, incl. vs Meth A tumor model and carcinogen-induced tumor mice; fight between cancer and immune system (elimination, equilibrium, escape) and survival of the fittest tumors (name “immunoediting”) portrayed by taking out immune system and tumors suddenly overwhelming previously healthy (mutagenized) mice and by transplanting tumors from immunosuppressed/competent mice to the other, respectively, with checkpoints being possible tumor tactic and other ways to engineer immune system). Story of ipilimumab (Allison’s anti-CTLA4 antibody for desperate metastatic melanoma, w/ BMS unsure about continuing, S vs. PFS vs. feeling better, side effects, approval in 2011, etc.).
  • Chapter 6 Tempting Fate. Mostly the anti-PDL1 approval story (“On December 10… [end of chapter]”). It’s also Brad (“[beginning]… help Brad save his”) and discovery of PDL1 (“Like most big discoveries… side of the handshake followed quickly behind”).
  • Chapter 7 The Chimera. CAR-T.
  • Chapter 8 After the Gold Rush
  • Chapter 9 It’s Time
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