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ASH – Novartis, Juno, June and Rosenberg steal the T-cell show

Date December 09, 2014

So stunning were the CART therapy data highlighted at ASH that it seems inconceivable that the meeting’s organisers declined even to feature them in a plenary presentation, let alone give them the star billing they deserved.

That said, a packed session on Sunday featuring two T-cell therapy pioneers, Dr Carl June and Dr Steven Rosenberg, was a plenary in all but name. The talk highlighted just how fast things have advanced here in the past year, and did much to explain the enthusiasm behind the flotations of Kite Pharma and Juno Therapeutics.

The star of ASH as far as CART (chimaeric antigen receptor T-cell) therapy goes was Novartis’s CTL019, a project in development with Dr June’s base, the University of Pennsylvania. Dr June highlighted a 39-patient paediatric relapsed/refractory acute lymphocytic leukaemia (ALL) study that produced nothing less than a 92% complete remission rate.

Dr Stephan Grupp, another researcher from the university, said CTL019 represented a viable strategy for long-term disease control, stressing a six-month duration of response of 76%, and six-month event-free survival of 70%.

Juno’s CART project JCAR015 was not far off: on Monday Dr Jae Park, of the Memorial Sloan Kettering Cancer Center, reported an 89% complete remission rate in 27 evaluable adult patients with relapsed/refractory ALL. After a median six months’ follow-up 12 patients remain disease-free, including seven with over a year of follow-up, and seven without a subsequent hematopoietic stem cell transplant.

Juno recently announced plans to raise $150m in an IPO, hot on the heels of Kite’s own flotation, which brought in $147m (ASH preview – CART comes of age, December 1, 2014).

At ASH the NCI’s Dr Daniel Lee reported data from a study of Kite’s KTE-C19 in 21 adults and children who were also relapsed/refractory. Overall complete response was seen in 67%, while in those with ALL the rate was 70%.

Low-hanging fruit

CART therapy involves ex vivo modification of the genetic makeup of patients’ T-cells to make them express a chimaeric receptor, before reinfusing them back into the patient. Since CD19 is present almost universally on B-cells it is this antigen that has initially been targeted by CART, and B-cell malignancies have presented the low-hanging fruit.

There are slight variations in the makeup of the chimaeric receptor and the gene transfer technology used by the various groups, and the fact that a lot of this work was initially shared by academics has led to messy litigation now that CART therapy is in the hands of corporate entities.

A slightly different approach, the Sleeping Beauty gene transfer system, is still held solely by academia, namely the MD Anderson Cancer Center. The hospital’s Dr Partow Kebriaei presented data in various malignancies, either with or without transplant, and intriguingly using CART cells derived either from the patient or the donor.

Dr Kebriaei highlighted Sleeping Beauty’s safety, in particular the lack of the notorious cytokine release syndrome, and possible cost advantages. Cytokine release and neurotoxicity, both correlating with disease burden and response, featured heavily at all CART presentations, though speakers agreed that the former was controllable with steroids and anti-IL6 therapy.

A separate consideration is whether CART therapy simply delays the time until patients are transplanted, or whether it is a replacement for transplant. Dr Lee, presenting the Kite data, called CART a “bridge to transplant”, but in the Juno study only 10 patients proceeded to transplant, while with Novartis’s CTL019 the number was just three.

“I would love CART to be a replacement for transplant,” said Dr Grupp. “This is my fondest hope, but we’re not there yet.”

Both in the Novartis and Kite trials some relapsing patients were enrolled into separate treatment with a CD22 CART, though interestingly this approach now seems to be in the hands of Juno, after a deal signed last week with a company called Opus-Bio.

Dr Grupp drew a distinction between relapses that are caused by loss of target cells’ CD19 protein – “antigen escape” – where continued presence of CART cells is seen, and so-called CD19-positive relapses, in which the levels of CART cells in a patient wane.

Non-plenary plenary

At the special scientific session on Sunday Dr June spoke of the development of a “CAR fleet” that involved targets beyond CD19, including CD22, EGFR and CD20, as well as combination approaches, in haematological malignancies and solid tumours too.

But, while T-cell development has come on in leaps and bounds, remarkably it is still the beginning of what might be possible, with engineered tumour-infiltrating lymphocyte (TIL) therapy representing the next frontier. “I believe both [CART and TIL] will be approved in several years,” said Dr June.

TIL therapy is the speciality of Dr Rosenberg of the NCI, which has a collaboration on it with Lion Biotechnologies in addition to its CART work with Kite. In a fascinating presentation Dr Rosenberg outlined what he called “living treatments” – autologous engineered T-cells that were tailored individually to a patient’s specific immunogenic mutations.

One difficulty is that each patient has tens of different mutations, only some of which are immunogenic; these must be identified – something Dr Rosenberg said he was doing using “tandem minigenes”. However far a therapy might still be from the market – not to mention the cost implications and manufacturing hurdles – results in individual patients have been striking.

Yet another T-cell approach, allogeneic CART therapy, is being pioneered by Cellectis in UCART19, a project partnered with Pfizer, and one of the advantages of such an off-the-shelf therapy would be cost.

EP Vantage spoke to Cellectis’s vice-president of CART development, Julianne Smith, who said UCART19 was a typical second-generation CART, but additionally involved gene editing to remove TCR-alpha on T-cells’ surface to avoid graft-versus-host disease. But clinical trials will not start until next year.

This is more relevant than ever now that the T-cell field is in Dr Rosenberg’s words “moving at warp speed”. The TIL approach takes personalised medicine to its logical conclusion, creating a new “drug” for each patient, and if this really is the future then it could make autologous therapy obsolete.

Selected CD19-targeting CARTs presented at ASH 
Academic group  Company  Co-stimulatory domain  Vector delivery  Efficacy 
University of Pennsylvania  Novartis  4-1BB  Lentiviral  36 CRs in 39 paediatric ALL pts 
Memorial Sloan Kettering  Juno  CD28  Retroviral  24 CRs in 27 adult ALL pts 
NCI (NIH)  Kite Pharma  CD28  Retroviral  14 CRs in 21 paediatric & adult pts 
MD Anderson  –  CD28, now changing to 4-1BB  Transposon/transposase  4 CRs in 5 pts (adjuvant therapy) 
–  Cellectis/Pfizer  4-1BB  Lentiviral  Preclinical data 

To contact the writer of this story email Jacob Plieth in San Francisco at jacobp@epvantage.com or follow @JacobEPVantage on Twitter

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