CTA:  Yes, that seems it could present a feasibility issue.

I’ve heard there can be up to 9 or 11 prior lines of therapy before CAR-T; it seems there’s an average of at least 3 different prior therapies that are typically tried before CAR-T.  Do you think introducing CAR-T earlier in the whole drug treatment scheme would be of value?

Dr Levine: Yes. And Novartis has trials in second-line ALL [acute lymphoblastic leukemia] that are opening (ClinicalTrials.gov Identifier: NCT03876769). And so that, I think, is going to happen, especially as we go to manufacturing improvements with more automation that hopefully will reduce the cost of these therapies. And definitely, as you go earlier, you have healthier T cells, and you have more patients from whom you’re likely to be able to successfully manufacture the product.

CTA:  Is that based on the theory that there will be antigen there, still, and so that will help with the creation of a better product, or…?


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Dr Levine: It’s not that — it’s the effects of the disease on T cells and the effects of the multitude of chemotherapy and biologic therapies on the quality of T cells. David Barrett, MD, PhD, at Children’s Hospital has published3,4 about the effect of prior chemotherapy on T-cell fitness; that we know that chronic lymphoid leukemia [CLL] has an adverse effect on T-cell function and disrupts the immune synapse. And in CLL patients, there [are] generally defects in the repertoire of T-cell specificities.

Now, we can correct for that somewhat, but again, [administering CAR-T] to patients who are not receiving 10, 11, or 20 prior lines of therapy makes it more likely that we’re going to be able to treat them with autologous CAR-T cells.

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CTA:  Are there any negatives from introducing CAR-T later in a regimen that perhaps have not been borne out yet?

Dr Levine:  Well, I guess the negative would be cost and how that figures in. There were a couple of abstracts on cost and value, and Richard Maziarz, MD, at Oregon Health Sciences University in Portland, has done some work in this area.5

If you compare the cost of allogeneic stem cell transplants to CAR-T cell therapies, and you [look at] average cost, then even that’s not the comparison, because the patients who have received so many prior lines of therapy (the relapsed and refractory, no-good-option patients) are those patients who are in the top quartile at least when one looks at the cost of allogeneic stem cell transplant.

So, over a 5-year period — and again, for those patients who survive, because there is significant mortality — but over a 5-year period, those are the patients who incur costs to the health system of $750,000, $1 million, even $2 million over 5 years.5 So, then when you’re comparing [that] to the cost of CAR-T cells, even in complex cases, it doesn’t look so bad.

CTA:  Are there any new developments in [UPenn’s labs] that you are especially excited about, or are there any new developments that you haven’t really publicized so much yet?

Dr Levine:  What we’re working on is approaches in solid tumors. I mentioned we have the clinical trial with dominant negative TGF-beta receptor. We’re working on combination CAR-T cells in myeloma and in ALL. We just opened up a CD22 trial, and we’ll combine that with CD19 (ClinicalTrials.gov Identifier: NCT03620058). It’s not the approach of having both on the same CAR, which the Stanford group is doing, but it is a double-CAR trial.  We also have that going on in myeloma, where we are combining BCMA with CD19 (ClinicalTrials.gov Identifier: NCT03549442).

Now, what’s interesting about that is that most myeloma cells — virtually all of them — do not express CD19, but there are reports of CD19 being expressed on a myeloma stem cell, and we have published on a trial where we treated myeloma patients with CD19 only after an autologous stem cell transplant.

Another type of improvement stems from our trial in CLL that started in 2010, and the overall response rate is about 45% to 50%, and the complete response rate is around 25%.  That’s far below where we are with ALL, and in particular, [in] pediatric ALL.

Now, as that trial was ongoing, we were looking to make improvements. We’ve made some manufacturing improvements, and we’re removing regulatory T cells and adding IL-7 and IL-15 to the culture to induce and encourage the growth of central memory T cells.

But also, around that time, the results from the clinical trials of ibrutinib were coming out, and it turns out in work that was done in the lab of Saar Gill, MD, PhD, with Marco Ruella, MD, Joe Fraietta, PhD, and in collaboration with John Byrd, MD, at Ohio State, we got samples from patients who were on ibrutinib but failing because the question was asked, with some rationale, could ibrutinib improve T-cell function?  And the short answer is: Yes.

And so, based on those preclinical studies, Dr Gill started a clinical trial in patients who were on ibrutinib but failing. And those are the results that Dr Gill presented [at the 2018 ASH meeting]. If you saw it, you saw that it looks very good … in fact, much, much better than the first trial. 

The next piece of new work that I can mention is in AML, or acute myeloid leukemia. And [in AML] there are antigens, but they are antigens with problems, meaning they’re expressed in other tissues. And in the case of CD33, [it is] expressed on the hematopoietic stem cell.

Now, if you were to give a CAR-targeting CD33 to a patient, that would kill AML, but it would also give the patients the equivalent of aplastic anemia because it would kill all of their stem cells. So, how do you prevent that? Well, the idea is to CRISPR out CD33 from the hematopoietic stem cell and give the patients an allogeneic hematopoietic stem cell transplant with their CD33 knocked out, and then come in with the CAR-33 cells. 

That’s in preclinical studies, and in 2020 we hope to be able to open that clinical trial … there is an answer to your question, I hope — [answering] not only what’s coming along, but how can we combine gene editing with CAR-T cells.

CTA: Following the use of CRISPR, are you going to be sequencing patients to confirm that CD33 has really be eliminated?  What’s the strategy to make sure that [the use of CRISPR is] safe?

Dr Levine: Well, all you would need is a sufficient number of hematopoietic stem cells that lack CD33 to be able to reconstitute the hematopoietic compartment. And the work that Dr Gill has already published has demonstrated that CD33 is not required for myeloid function, and that hematopoietic cells in which CD33 is CRISPR-ed out are immune or are not killed by CAR-33 T cells.6

Disclosure: Bruce Levine declared he has financial interests in the form of intellectual property and patents in the field of cell and gene therapy, as well as relationships with: University of Pennsylvania Alliance with Novartis; CRC Oncology, Cure Genetics, Novartis, Terumo, Avectas, Brammer Bio, Incysus, Vycellix, and Tmunity Therapeutics.

Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight.

References

  1. Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24(10):1499-1503.
  2. International Society for Cell and Gene Therapy. ISCT statement – human genome editing. Published December 7, 2018. Accessed April 24, 2019.
  3. Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci Transl Med. 2016;8(320):320ra3.
  4. Das RK, Vernau L, Grupp SA, Barrett DM. Naive T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers. Cancer Discov. 2019;9(4):492-499.
  5. Maziarz RT, Guérin A, Gauthier G. Five-year direct costs of acute lymphoblastic leukemia pediatric patients undergoing allogeneic stem cell transplant. Int J Hematol Oncol. 2016;5(2):63-75.
  6. Kim MY, Yu KR, Kenderian SS, et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell. 2018;173(6):1439-1453.e19.