CAR-Ts take centre stage again

The CAR-T therapies approved and on show at ASCO 2018 represent the first in what could be a new wave of powerful cell therapies
Bluebird Bio and Celgene drugs’ new mechanisms of action take aim at improved efficacy and reduced toxicity
Research into a different type of CAR-T targets solid tumours to overcome the physical barriers that prevent infiltration by the immune system

Chimeric antigen receptor T-cell (CAR-T) therapies continue to blaze a trail in cancer care, with new results at this year’s ASCO meeting from major players such as Bluebird Bio and Celgene. Richard Staines reports.

Chimeric antigen receptor T-cell (CAR-T) therapies have already been named ‘advance of the year’ in the American Society of Clinical Oncology (ASCO) annual report for 2018 and, although there are only two approved CAR-T therapies on the market, there are many more in development.

CAR-T therapy involves a patient’s own T-cells being harvested and genetically modified so that they can detect a target on cancer cells. They are then injected back into the patient and left to seek out and destroy the malignant cells. At the moment they are only approved for use in a few blood cancer indications, but the hope is that their use will be expanded into new blood cancer uses, and possibly solid tumours.

While the treatment is powerful, it does have drawbacks – it can cause the immune system to go haywire, potentially causing cytokine release syndrome (CRS) or other toxicities that can be life-threatening if they are not managed properly.

At ASCO this year, there was data from Celgene’s partner bluebird bio on a CAR-T that works on a different target from already approved therapies. Celgene also had new data on the lead candidate from Juno Therapeutics, a CAR-T company it acquired earlier this year.

Bluebird’s bb2121 therapy prevented very advanced multiple myeloma from spreading for 11.8 months – a progression-free survival figure that disappointed investors even though the patient group involved was extremely ill. Results were from a group of 43 patients with heavily pre-treated multiple myeloma in a phase I trial.

The trial is being closely watched because bb2121 has a different mechanism of action from approved CAR-T therapies from Gilead/Kite and Novartis. Both companies’ CAR-Ts drugs target CD-19, but bb2121 zooms in on an antigen known as B-cell maturation antigen (BCMA), which is found in both healthy and cancerous B-lymphocytes. Safety looked manageable even at the highest dose of around 800 million cells, Bluebird said.

Joshua Sasine, director of UCLA Health Medical Center’s CAR-T programme, was more enthusiastic about the results. He told pharmaphorum:

“It looks great. That was a very impressive response rate to say the least – but we need to see the duration of the response. It was also good that we could go that high in the dose without much toxicity.”

Meanwhile latest data from Juno’s JCAR017, also known as lisocabtagene maraleucel, shows that serious safety issues and deaths, which led to trials of its other CAR-T being axed, have not been an issue. Juno is testing the treatment, nicknamed liso-cel, in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma – a disease where both Novartis’ Kymriah (tisagenlecleucel) and Gilead/Kite’s Yescarta (axicabtagene ciloleucel) are already approved.

With JCAR017 Cytokine release syndrome and neurotoxicity were observed at a rate of 37% and 23% for all grades, and 1% and 13% for grades 3 and 4, respectively.

This is a more benign safety profile that could lead to the drug being used in outpatients, unlike already approved therapies where patients spend a lot of time after treatment in specialist clinics.

At six months, 49% of patients on liso-cel remained in remission, with 46% maintaining a complete response in this cohort – 37 patients in all. Results from the TRANSCEND trial have prompted Celgene to talk up the CD-19 targeted drug as a potential best-in-class therapy. The cohort that Celgene hopes will produce data leading to FDA approval is fully enrolled, paving the way for a potential launch if all goes well.

With several CAR-Ts now in the pipeline along with those already approved, UCLA Health Medical Center’s Sasine is optimistic about the potential of the treatment in the future. Despite the high costs of CAR-Ts – up to $475,000 for Novartis’ Kymriah, Sasine said the therapy makes sense and that the efficacy seen in some patients outweighs the risks of the side effects.

“If you think that a small molecule gives you a low response, the decision is very easy. If you pick between that and the CAR-T, which gives what seems to be a much greater chance of remission, I would prefer giving the latter.”

On the side effects, Sasine agrees that while they are a challenge to manage, CAR-Ts are a better alternative than previous standard of care. “It can be very serious, along with the high burden of disease, it can be very difficult to manage at times. It is a problem no question about it.”

With CAR-T therapies, many of the safety issues occur early in treatment, instead of further down the line as with older drugs. Furthermore, Sasine said that overall mortality rates are higher on standard therapy. This is because patients tend to get severely ill over time, with a high chance of dying, instead of having a good chance of going into remission if CAR-T therapy is successful.

Tackling solid tumours with CAR-Ts

But there are other potential drawbacks with CAR-Ts too – the process of manufacturing the T-cells takes weeks and they have not yet been able to produce results in solid tumours. At the moment CAR-Ts are best suited to blood cancers because of the antigens that they target, and because they have issues penetrating the environment surrounding tumours. Tumours evade detection not just by using biochemical switches, but by creating physical barriers that prevent infiltration by the immune system.

However, Adaptimmune has partnered with GlaxoSmithKline (GSK) to try and produce a different type of cell therapy, called T-cell receptor (TCR) therapy, that has a strong enough affinity with tumour cells to overcome these barriers. TCR therapies recognise peptide fragments from proteins present inside and on the surface of the cell, allowing them to target a larger number of proteins, compared to CAR-T therapies.

Adaptimmune had early-stage data from its NY-ESO SPEAR T-cells in patients with myxoid/round cell liposarcoma (MRCLS) – a rare cancer that can occur in the limbs and predominantly affects young people. Only eight patients have been treated in the pilot study, and so far there have been three confirmed partial responses, one unconfirmed partial response, three patients with stable disease, and one recently treated patient awaiting assessment. GSK has taken an option to research, develop and market the technology, and the transition phase is ongoing.

Dr Rafael Amado, chief medical officer at Adaptimmune, told pharmaphorum:

“Most of the patients in our trial had received at least four prior lines of therapy and had few treatment options remaining. To see responses in this notoriously ‘cold’ tumour is very encouraging.”

A study of another cell therapy known as MAGE-A4 is ongoing, and Adaptimmune has added synovial sarcoma and MRCLS to a trial programme that includes nine solid tumour indications.

Off the shelf CAR-T therapies

But the CAR-T therapies approved and on show at ASCO represent the first in what could be a new wave of powerful cell therapies.

While technically impressive, making a personalised therapy from a patient’s own T-cells is a costly and time-consuming process. UCLA’s Sasine says that the next wave of cell therapies, which will be from ‘off the shelf’ sources and could be produced and stored in bulk, could have significant advantages over existing therapies.

The much lower cost of off the shelf, or allogenic, therapies is one clear advantage. But Sasine said he would be looking for the next generation to be even more effective as they could be derived from stronger precursor cells. The T-cells used in approved therapies have been floating around in patients for years, and may have already had to withstand several lines of cancer therapy, Sasine said.

“The biggest benefit is the fact that we can use much younger, healthier cells. CAR-T patients are often older and fundamentally a young person has a higher functioning thymus (the organ that stimulates development of T-cells).”

“If you can use those cells then you overcome many of the disadvantages of using a patient’s own T-cells,” he added.

In theory all this could translate into cheaper therapies – but only if companies that improve on the efficacy currently shown by approved treatments don’t decide to demand more money as a result.

Sasine said that companies that bring the next generation of cell therapies to market should think carefully about how they justify their price. He concluded: “If they are doing the same thing (in terms of efficacy) the only benefit is a faster turnaround time.”

Richard Staines is Senior Reporter at pharmaphorum. He has been a journalist since the 1990s and has written for websites, newspapers and magazines. He has always had an interest in health, and has been focusing on the pharma industry since 2010, interviewing industry leaders and covering stories on topics including regulation, mergers and acquisitions, and the latest clinical developments.

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