Bob writes:
Kudos on this episode on CAR T immunotherapy: it was wonderfully detailed and absorbing.
At one point the discussion touched on regulatory T cells and the autoimmune response. I am interested in this area of immunology since my daughter has late onset type 1 diabetes, thought to be an autoimmune disease.
A recent article in Scientific American (Feb. 2018, p.55) speculates that an enterovirus infection similar to polio is involved in triggering the response.
Here we have a perfect confluence of topics dear to podcast members, viruses and the immune system! Might it merit a show?
Regards, Bob
Neeraj writes:
Hi ImmunoModulators,
I hope your 2018 is going great so far and I was absolutely thrilled to listen to the most recent Immune podcast on CAR-T. This is truly a remarkable breakthrough and I am glad that you had such a nicely outlined and detailed discussion on the same. Cancer plagues humanity at so many different levels and to have a breakthrough like this actually transform into curable therapies is totally miraculous (both at a molecular and emotional level). I realize that this technology is still at its infancy and but I am certain that with time, alterations will happen, that will make it safer, more efficacious and most importantly “affordable”. The current price tags (whether it’s for the Novartis’ or Gilead’s therapies), are obviously exorbitant but given the immense technological challenges one overcomes in performing them, are probably a bit justified. At times it’s easy to demonize the drug companies (and YES epipen price escalation was hideous), but currently working at one, I can vouch that this is an incredibly capital intensive enterprise. When things succeed, it looks great but one never sees the countless dollars and man hours that went into overcoming challenges that don’t succeed. Yes we learn from failures, but when the investors and stakeholders are breathing down your neck, it ain’t always as memorable when your R&D efforts fail to justify the research undertakings. I think that detail is sometimes amiss to the broader audience and just seeing an exorbitant price tag for an approved therapy can at times, certainly influence mindset. But CAR-T, even at this early stage, feels like a unique opportunity that is moving ahead at breakneck speed. And I hope for patients this is just the start with many more improvements in the near to long term. And in light of talking about progress towards treating cancer, I am in agreement with Dr Racaniello about his recommendation for the book “Emperor of all maladies”. This is probably one of those books that everyone wanting to learn or having impacted by cancer, should Absolutely have on their reading list. In my opinion, it is one of the best orations of the history of a field of scientific investigation as diverse and ancient as Cancer. For me, it is second only to the history of how genes were discovered and our understanding of the circadian rhythms as listed in Time, Love and Memory by Jonathan Weiner. Thus in closing, I would like to personally thank you for taking the time from your busy schedules to release these podcasts (this doesn’t include you Steph, as being a graduate student, your time right now has no intrinsic value except when the experiments succeed J. I guess that’s pretty much how most grad students feel). Overall, the entire Twi(mmune)X series is something that every curious soul should listen to as I am certain that it will benefit you in ways you can’t even fathom. Thus keep up the great work and I hope you find more sponsors for these pearls of wisdom.
Best,
Neeraj
P.S: And maybe (just a suggestion), someday you can have a discussion on Flu and why it has been so hard to generate highly efficacious vaccines to induce long term immune memory against this seasonal epidemic. It is probably not as tricky as Dengue, but nonetheless, it overcomes our immune surveillance quite effectively if you are not vaccinated (or at times even when you are).
Neeraj Kapoor, Ph.D.
Scientist II
SutroVax, Inc.
Yesol writes:
Hello Vincent, Cindy, and Steph,
I cannot thank you enough for creating the Immune podcast! While I listen to all TWi-X shows, immunology is something I have always been fascinated by. I’m not a scientist (yet) but an oncology nurse, and so the content is more familiar and relevant to me. I am especially thankful for the CAR-T episode! I have been closely following recent developments in immunotherapy of the past few years, and CAR-T cell therapy is by far the most mind-blowing! I especially appreciate your effort in presenting the material in an everyday language without dumbing things down. Some of the classes I teach at our hospital include immune system, stem cell transplant, and chemo drugs, and I am learning a lot from you not only the content but also how to present effectively for non-scientists.
Because I enjoyed this episode so much, I have quite a few comments.
First, there was a question why Kymriah is indicated specifically for children and young adults. It seems to me that it just has to do with the fact that it’s approved for acute lymphoblastic leukemia (ALL), which primarily affects young people. As Cindy described, ALL is often curable, but there is a small subset that is difficult to treat and treatment options are limited for relapse and refractory diseases. There are four major types of “leukemia” and they have different epidemiology and characteristics which I summarize below (source: William’s Hematology, 8th ed):
- Acute myelogenous leukemia (AML): predominantly affects adults; about 9000 with AML die annually in US; treated with chemotherapy and stem cell transplant but cure is difficult in older adults
- Chronic myelogenous leukemia (CML): predominantly affects adults with increasing incidence with age; about 5000 incidents in US; CML used to be a death sentence (rarely surviving beyond 2 years after diagnosis) but now life expectancy is almost close to normal since the introduction of the tyrosine kinase inhibitor, imatinib in the 80’s. It’s amazing how a once-a-day pill changed the lives of those with this disease!
- Acute lymphoblastic leukemia (ALL): 61% of ALL cases are diagnosed before the age of 20 years; most common malignancy in children younger than 15;
- Chronic lymphocytic leukemia (CLL): Median age of onset 67; treated with chemo and monoclonal antibodies; no cure
Yescarta by Kite, on the other hand, is indicated for diffuse large B cell lymphoma, which occurs in adults. I am curious though, why two different agents for two different diseases? If both agents can recognize CD19, wouldn’t that mean they can be used for any cancers of CD19+ cells?
I’d like to also make a comment about implications of all these new immunotherapy agents, like checkpoint inhibitors, and CAR-T cells. Because their side effect profile is drastically different from what people are generally familiar with from cytotoxic chemotherapy, educating the public — not only the patients, but also healthcare professionals beyond oncology — is critical. Patients must understand how important it is to report even “benign” symptoms, maybe a little bit of skin rash or diarrhea — which may seem like nothing at first but can be a sign of a more serious inflammatory immune response. I’ve also heard of fatal cases where non-oncology physicians failed to recognize the signs of inflammation due to checkpoint inhibitors and it was too late by the time the patients’ oncologists were contacted.
By the way, a question for Cindy: have you encountered a drug called blinatumomab during your research for this episode? In my mind, I thought of this drug, which we started seeing last year, as the precursor to CAR-T cell therapy. It’s called bi-specific T-cell engager (BiTE) and has CD19 and CD3 binding sites. Would you say this is the same thing as the bi-specific antibody discussed in episode 3? Also, blinatumomab is a slow continuous infusion for 28 straight days. Patients go home with a portable infusion pump, which isn’t very convenient. Any idea why this is necessary?
One last comment: I ran into this paper (https://www.nature.com/articles/s41598-017-00462-8) some time ago, which explores combination of PD-1 checkpoint inhibition using CRISPR/Cas9 and CAR-T cell. It’s a straight-forward experiment (well, speaking from a person who has no idea what entails to conduct wet-bench experiments…) and logical next step of sorts… On the other hand, it seems like a scary idea to me to permanently disable the checkpoint function of T cells that are being released out there to kill stuff, especially if we know that the transferred CAR-T cells still circulate in the body even after ten years. I’d love to hear your thoughts as to the pros and cons should this become a reality clinically.
Thank you again for everything you do!
Your fan from Los Angeles,
Yesol
P.S. Would you consider an episode on graft vs host disease? Coming from a bone marrow transplant nursing background, GVHD is one thing I both love (for its mechanism) and hate (for what it does to people.) I’ve had patients whose skin literally sloughs off (acute GVHD) to those who die slow, agonizing death from bronchiolitis obliterans (chronic GVHD). Emotional aspects aside, I would love to know what exactly the immune cells do in the body to bring these effects.
Mark writes:
Episode 4 was amazing. The presentation on Car-T cells was outstandingly well presented, and the subject matter blew my mind. After the episode, I spent hours pondering in amazement.
Could I ask, is it correct that T-cells initiate cell death in a different way than occurs during Apoptosis. In Apoptosis, there’s a managed deconstruction process which occurs within the cell, right? I’m guessing that T-cells employ more of a demolition process, than a deconstruction process. To use an analogy, blowing up the cellular building with explosives, rather than taking it down floor by floor with power tools. The resulting debris setting off the immune system.
Also, another thing, when you guys talk about allergies, could I ask a preemptive question that you might be able to work into that discussion somehow?
I receive allergy therapy in the form of a monthly set of injections that takes around 5 years. It’s for seasonal allergies to pollen, cats, and a dust allergy. If I already have memory B-cells generating the wrong response to allergens, how does this treatment work to reduce the population of those B-cells? Maybe someone can develop Car-T cells to target the BCR of cells which match a particular antigen to quick reset the B-cell population, instead of 5 years on injections.
Keep up the amazing job, this is my favourite of Vincent’s podcasts, and I’ve listened to them all. Simply because the subject matter of the human immune system is so awesome.
Thanks,
Mark
New Zealand
Ana writes:
Dear Cindy, Steph and Vincent,
Thank you for starting this podcast! Immunology is one of those simultaneously fascinating and daunting subjects for me. I remember writing a short essay at uni about dendritic cells and finding it so interesting but also so complex that it was hard to make sense of all those cells, molecules and pathways. I am afraid I am still a complete ignorant of the subject many years later.
I have a question. It has been repeatedly shown that breastfeeding is beneficial for babies, helping to protect them from pathogens and even stimulating the development of their immunity. However, working with measles (as a virologist) I know that, for instance, if the MMR vaccine is given before the recommended 12 months in the context of an outbreak, it should be given again at the recommended age as the maternal antibodies present in the child limit the effectiveness of that early vaccination. This made me wonder how does the passive immunity gained from maternal antibodies (before birth and through breastfeeding) work with/for/against the child’s own active immunity?
I know this does not relate to any of the previous podcasts, so feel free to ignore it or keep it to a later/more relevant episode!
Many thanks for getting this podcast going,
Ana, fully immunised