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Kite’s Latest News

Readers will surely recall the problems that surfaced last year with Juno’s CAR-T cell therapy program. There were a number of patient deaths, and worried onlookers were wondering how their competitor, Kite Pharma, was doing. Well, now there’s word that a patient in one of their trials has died from what’s described as multiple organ failure followed by cerebral edema (which is a combination that would certainly do it).

It would be safe to describe the state of mind today for researchers and investors in this area as “jumpy”. Chimeric antigen receptor T-cell therapy is an extraordinary field, which has so far basically pulled some patients practically out of the grave. But the immune system is (1) extremely powerful, (2) not anywhere near being completely understood, and (3) quite variable from person to person. That last part might be the biggest barrier, because it looks like we’re going to need to have a better handle on how individuals will react to the engineered T cells. As it stands now, responses range from “This therapy will save your life when nothing else can” though “This therapy will slow down your cancer to an unpredictable degree” all the way to “This therapy will kill you, even faster than your cancer will”. One would want some clarity about which of this situations is most likely to result. KITE stock is down over 12% today as I write.

A related note: doesn’t this sort of thing make you roll your eyes, even more, about all the hundreds of “nutritional supplements” that promise to Boost Your Immune System? Believe me, for most people, a boosted immune system is not what you’re looking for. . .

15 comments on “Kite’s Latest News”

  1. Hap says:

    I know of someone who has been through two rounds of (these or similar) therapies; the cancer dropped the immune markers and was unperturbed. It still sounds neat, but cancer’s been playing the “beat the immune system” game for awhile.

  2. MAP says:

    I, for one, think that it is important to understand the patient population and the risk of not treating the disease. One patient death is always one more than you would like to have. But these patients are very sick and the early roads will be rocky. I think it does the field a disfavor to keep highlighting the negative news in this area.

    “Kite reveals in its latest 10-Q that one of 30 patients in a safety expansion cohort developed multiple organ failure and then fatal cerebral edema; Kite says the incident was the first grade 5 cerebral edema event that has occurred in ~200 patients who have been treated in the ZUMA clinical trials.”

    As we all know, traditional chemotherapy is also highly toxic and can be lethal. In that sense, I am not sure that immunotherapy drugs are that much different.

  3. F says:

    The problem is that these type of passive immunotherapies completely take over the patient immune system and are therefore very difficult to control. Perhaps more active approaches that only kickstarts the patient’s own immune system or gives it a push in the right direction (e.g., neoantigen vaccines and checkpoint inhibitors), might be the way to go.

  4. Christophe Verlinde says:

    Fifteen years ago my immune system went haywire. At the time it took 6 ivs with 1 GRAM of methylprednisolone, a week of IGG administration, and finally 6 rounds of plasmapheresis to calm the immune storm. An uncontrolled immune storm can kill you in no time.

  5. UudonRock says:

    These Kite trials have been running for over a year now and for the most part the fact any of these subjects are coming into 12 months is rather substantial considering their general prognosis. Now I would hesitate to say they had X months of time as there is no real way to know with any certainty. This kind of therapy is problematic and neurological toxicity leading to edema and aseptic meningitis were a known possibility. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063985/ That being said it is never encouraging to think it was the therapy that caused it. The market doesn’t really care about the cause though, just the fact that it could be. Considering Juno any hit was bound to be a hard one. I think the largest issue with this kind of therapy (and almost every other) is the uniqueness of every tumor. While the WHO provides guidelines on the classifications for each lymphoma, the treatments are very much not written in stone. Many may be anchored in bone marrow and the lymphatic system, but they are not exclusive and involvement anywhere else in the body, including the CNS, is not uncommon, particularly with large B-cell types which seems to be what most of these trials are geared towards. I’m not certain if a baseline CSF was performed on this unfortunate subject, but considering the risk one would hope it was standard practice. A baseline could help to either quell the concern about the therapy by showing an underlying pre-condition, or confirm the worst.

  6. steve says:

    The real question is whether this is on-target or off-target toxicity. It’s possible that there were leukemic cells in the CNS of this patient and the CAR-T cells killed them as they should but the resulting inflammation in the brain caused the cerebral edema. It’s also possible that some patients express CD19 in some cells of the CNS. Finally, it’s possible that this is non-specific brain inflammation that occurs. Let’s not throw up our hands and just say that the immune system is complicated. It’s important to pin down the cause of the neurotox and address it. This is unfortunately the growing pains that comes with any new therapeutic modality and it takes years to learn how to apply new technologies appropriately. Most advances in chemo came this way, with painstaking approaches to come up with combo therapies that reduced bone marrow and gut toxicities. It will be the same with immunotherapy and only clinical research will allow for optimized protocols. Unfortunately, some will die along the way but others who would have died will be saved, as has already happened in these trials.

  7. Anonymous says:

    These drugs are given knowing it will set off a cytokine storm in a patient already weakened by cancer. The hope is they can be supported through it. Those efforts are not always successful. Is this an a reasonable approach to cancer treatment? Given that the standard therapies, including and especially bone marrow transplants, come with a heavy dose of “The cure may be as fatal as the disease”, I can’t answer that easily.

  8. jerry keyes says:

    Sounds like the cytokine storm was the culprit in this case. Ziopharm controls these cases with the Rheoswitch which modulates the effect of the drug to keep it at a safe level. Their Sleeping Beauty can start or stop the drug response in 15 minutes.

  9. steve says:

    Cytokine storms are managed by steroids and IL-6 blockers (Tocilizumab). The neurotox appears to be different. Again, chemo tox (bone marrow and gut) had to be managed as well. Oncologists understand that it’s very difficult to distinguish normal versus tumor cells and there is no magic bullet that kills cancer cells that doesn’t have associated toxicities. By the way, this may not just be a CAR-T issue, anti-CD19/CD3 bispecific antibodies (Blinatumomab) also has neurotox side effects.

  10. Alex says:

    Steve, your responses are exactly why some form of modulation is required to establish a safe and predictable method to traverse toxicity. FDA should be hesitant to approve an always-on CARt. KITE may have moved further along than JUNO but they both share the same common issues which, IMO, should have been addressed before moving further along.

    1. steve says:

      Agreed. Being able to turn on and off a response is a definite advantage and second-gen companies have this. Ziopharm says they can do that with their rheoswitch technology; other companies like Bellicum have suicide genes. Companies are also moving to universal CAR-T technologies for off-the-shelf products though the jury is still out about this. The big issue in the field, aside from the tox problem, is how to generate immune responses in “cold” tumors where the mutational load isn’t high enough to generate an immune response. This also feeds into the tox issue as there aren’t very many uniquely tumor-specific antigens. CD19 isn’t tumor-specific, it’s B cell specific so you wipe out normal B cells along with the malignant ones. This clearly isn’t possible for lung, liver or other tumors where you can’t just wipe out the normal cells along with the cancer. This is a huge and emerging field where technology is rapidly developing so general pronouncements will often be obsolete by the time they’re uttered. Chemists can play an important role as more and more is learned about how tumors shield themselves from immune responses (i.e., this is a target-rich environment and IDO is not the only game in town for small molecule drugs).

  11. NJBiologist says:

    “A related note: doesn’t this sort of thing make you roll your eyes, even more, about all the hundreds of “nutritional supplements” that promise to Boost Your Immune System? Believe me, for most people, a boosted immune system is not what you’re looking for. . .”

    Oh, but it’s OK–those supplements reduce inflammation while boosting your immune system.

    Yeah, I couldn’t even type that with a straight face.

    1. Mike Andrews says:

      OhYeah! I have RA; it apparently was triggered by Rickettsia from a tick bite. My wife got Lyme from a tick on the same outing, and that apparently triggered her RA. Yep: we both have it. An overactive immune system is EXACTLY what you want to not have. Now she’s on Enbrel once a week, which is next thing to magic for her. I’m on Humira, just stepped up from once every other week to once a week; it, too, is a magic bullet, as much as Ehrlich’s Salvarsan.

      But if we could find something that DIRECTLY modulated the overactive parts of my immune system, I’d be jumping up and down to get on it.

    2. Lane Simonian says:

      Not quite as crazy as it sounds. Peroxynitrite in part via DNA damage causes inflammation. Peroxynitrite may also play a role in allowing tumors to escape immune responses. Scavenge peroxynitrite and you both reduce inflammation and increase the body’s own immune response to tumors.

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