Developments in CAR T treatments for adult patients

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Published: 3 Dec 2018
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Dr David Miklos - Stanford University, Palo Alto, USA

Dr David Miklos speaks to ecancer at ASH 2018 about three different presentations on cancer cell therapy in the CAR T arena in adults.

He outlines some of the methods, results and next steps for these studies, as well as potential implications for patients - all within a bigger framework of CAR T research.

Dr Miklos concludes there needs to be a national discussion about cost issues in order to reach more patients with these treatments. 
 

At this meeting our group is bringing forward three different presentations, all related to cancer cell therapy in the CAR T arena. As an adult doctor much of the focus has been on the commercial product rolled out in lymphoma, diffuse large cell aggressive lymphomas. For part of yesterday’s presentation for the real world, 274 patients have been treated with the commercial axi-cel since its roll-out in October 2017. I’m sure you’ve heard from a few of your guests by this point that the results basically showed in the setting where many of the patients had more comorbidities, had less eligibility meeting than the original clinical trials, the outcomes showed the exact same clinical benefit, again around 85% overall response rates and 50% complete response rates with durability that, of course, is more limited because we only have the commercial layout for about a year’s time but we’re very optimistic that the outcomes through six months looked exactly the same.
People want to know about toxicity, cytokine release syndrome, utilisation of the intensive care units are decreasing as physicians are becoming more comfortable with the treatment of the patients. However, really the concern of the neurological toxicity, that grade 3 neurotoxicity, less responsiveness, concerns for ICU visits, are still remaining at 30%, so that’s a limitation.

The last session that came from MD Anderson showed a really provocative finding, that is looking at 65 patients, 20 of whom were over 65 and the rest who were below. The benefit of the 65 year olds was just the same as those who were under 65 and that really raises the issue of how do we get the therapy out there, how do we get the Medicare reimbursement, how do we bring this life-saving therapy to those patients. But nonetheless, 40-50% complete response rate.

In fact, today Lancet Oncology is bringing the two year, of which I’m an author, results that show around 39% complete response durability at two years and that’s exciting but that’s not 100%. So others may have many ideas on how to improve this – you could add cytokines, you could armour the CAR, you could maybe make it a little bit more inducible, you could discuss the costimulatory. What we are most finding to be the problem, or at least the easiest thing to fix, and we have a poster tomorrow night with Dr Jean Oakes being the first author, showing in 16 patients who have disease progression after treating 36 patients with that commercial Yescarta that the progression is associated with antigen of CD19 loss. That should be obvious that when the antibody is only binding to the 8 amino acid epitope and that it is a heterogeneous collection of billions of cancer cells, there are some of the cells that are missing the epitope. It’s much like the Galapagos Islands and Darwin’s natural selection of the species, it wasn’t that the birds who had the narrow beak thought about it, they just were by chance born with a narrow beak and could reach the food between the rocks. Likewise these cancer cells that are without the CD19 expression are escaping this immunological effect and they will come back.
So 16 patients progressed, 12 were biopsied, 6 show loss of CD19, that’s a 50% problem. Quite easily the most simple thing to do would be target two antigens, not one. OK, so how do you do that? Well at Stanford with the work of NCI colleagues Terry Fry, Crystal Mackall, the now director of our cancer institute, we have been able to test in a phase I first in adult bispecific CAR antigen targeting both CD19 and CD22 in patients with relapsed refractory acute lymphoblastic leukaemia or diffuse large cell lymphoma. Patient accrual began in August 2017 and at this point 10 products have been manufactured, 9 patients have been dosed. So Dr Nash Hussein this afternoon will present those results showing successful manufacturing, in-house production, very low toxicity risks with only 4 patients having any toxicity and only 2 having any grade 2 toxicity. This very easily could be dosed in the outpatient setting, it is a 4-1BB costimulatory molecule. Most importantly, it’s a single chain polypeptide that binds both 19 proximally and 22 distally so there’s no escaping. It’s one protein that targets both, it’s not the bicistronic problem where maybe one outcompetes the other.

Obviously we have a lot of work to do. With the support of the California Institute of Regenerative Medicine giving us a $12 million grant we’ll now be rolling forward treating 70 patients in the expansion cohort beginning January 24th 2019. This is really a message to the patients – come find us. The therapy is effective, there’s low toxicity and this two is better than one.
That’s really one of the more exciting aspects. I want to get on my soap box for a second and make another comment and that is yesterday in the aggressive lymphoma we learned from two consortiums about the successful use of Yescarta across 384 patients. In that entire collection of patients not on clinical trial at centres of excellence but, again, nothing special, those patients endured three deaths. That mortality, non-relapse mortality risk, is very low. The expertise with which we are managing these patients is improving and what’s most concerning right now is that we think 12,000- 14,000 patients would be eligible for the therapy and less than 700 patients received therapy this year. So how do we get that word out to patients, their families, referring doctors? I hope ecancer can help us.

Is that a cost issue?

The cost issue is a concern, I don’t know how to answer that question. I’m from Stanford, we are treating patients irrespective of insurance, all ages, who have the ability to benefit. While the decreased response rates and overall survival were shown in patients who had a very poor performance status, it was evident that even those who have reduced performance status were getting clear benefit. We have a national discussion about how we allocate costs.
Then there’s the other question because maybe cost should be less, maybe there’s a different way to produce these cancer cell therapies and one of the models is distributed production which is consistent with our in-house prodigy based manufacturing of the CAR 19/22 plus other CAR T-cells.

So we don’t know where the economics of CAR T-cell are going to go but the lesson yesterday was they’re here to stay. They’re as effective as advertised and we have a few simple ideas on how to make them better.