Scientific breakthroughs, approvals: Latest CAR T-cell therapy related developments

By Jane Byrne

- Last updated on GMT

© GettyImages/Meletios Verras
© GettyImages/Meletios Verras

Related tags CAR-T Chemotherapy Leukemia lymphoma solid tumor

From new research offering promise for children's cancer to FDA registrations, we track the progress made in the past few weeks in terms of advancing CAR T-cell therapy in a number of markets.

Novartis on Friday [February 12] reported that it had received approval from Australian regulatory agency, Therapeutic Goods Administration (TGA), for Cell Therapies to manufacture and supply its CAR-T therapies commercially for eligible patients in that market.

The Cell Therapies manufacturing facility in the Peter MacCallum Cancer Center in Melbourne is now the first and only approved commercial manufacturing site for CAR T-cell therapies in Australia.

Steffen Lang, global head of Novartis technical operations, said international collaborations such as these are critical in accelerating advancements in areas of great medical need.

Local manufacturing means patients’ cells can stay in Australia without the need to ship them overseas, generating greater efficiencies and an expectation of quicker timelines tor eligible patients, said Novartis.

New BMS therapy approved in the US

Earlier this month, the US FDA approved Breyanzi (lisocabtagene maraleucel), a new CAR T-cell therapy for adults with relapsed or refractory large B-cell Lymphoma, produced by Bristol Myers Squibb (BMS).

Breyanzi is a CD19-directed CAR T-cell immunotherapy. It consists of autologous T-cells that are genetically modified to produce a CAR protein, allowing the T-cells to identify and eliminate CD19-expressing normal and lymphoma cells.

The TRANSCEND clinical trial evaluated Breyanzi preceded by lymphodepleting chemotherapy, in adults with recurrent large B-cell lymphoma after at least two lines of previous therapy. Of the 192 patients evaluable for response, the overall response rate was 73% with a complete response rate of 54%. Of the 104 patients who achieved CR, 65% had remission lasting at least 6 months and 62% had remission lasting at least 9 months, reported the company.

The estimated median duration of response has not been reached at the time of the approval. The estimated median duration of response among patients with partial response was only 1.4 months, it said.

Overall, 79% had significant side effects including neutropenia anemia, and thrombocytopenia. Instances of any grade cytokine release syndrome (CRS) occurred in 46% of patients at a median onset of five days. There were neurologic events that occurred in 30% of patients and 21% of patients received tocilizumab and corticosteroids, respectively, said the company.

BMS plans to manufacture Breyanzi ​for each individual patient at its cellular immunotherapy manufacturing facility in Bothell, Washington. To help support broad patient access, it also intends to launch Breyanzi ​across an expansive network of treatment centers. 

Greater patient access to cell therapy in the UK

In terms of developments in other territories, in January this year, the UK National Institute for Health and Care Excellence (NICE) recommended a new CAR T-cell therapy to be available to National Health Service (NHS) patients via the Cancer Drugs Fund.

The personalized treatment, called Tecartus or autologous anti-CD19-transduced CD3+, is produced by Kite.

New NICE guidance says the treatment can be considered for those with relapsed or refractory mantle cell lymphoma, who must previously have had a drug called Bruton’s tyrosine kinase (BTK) inhibitor, such as ibrutinib.

The limitations of first generation CAR T therapy 

A Morgan Stanley report​ on CAR T therapy, from August 2020, noted:

While first generation chimeric antigen receptor (CAR) T-cell therapy has shown impressive results curing blood cancers at significantly higher rates than previous therapies, issues such as high costs, complexity of treatment, and potential life threatening side effects have limited their use.

"Next generation CAR T-cell therapy made using pluripotent stem cells seeks to maintain first generation CAR T-cell therapy’s efficacy while reducing the issues that have limited adoption.

If successful, these advances in stem cell based CAR T-cell therapy could boost adoption and expand the addressable market for CAR T therapies into earlier line therapies and even into solid tumors while reducing the financial burden of the treatment and improving its safety." 

Research breakthroughs

Last month also saw some promising scientific advances in the field of CAR T-cell therapy research.

While CAR T-cell therapy has revolutionized leukemia treatment, unfortunately, the therapy has not been effective for treating solid tumors including childhood cancers such as neuroblastoma.

But scientists at Children's Hospital Los Angeles (CHLA) have now come up with a modified version of CAR T-cell therapy that they say shows promise in targeting neuroblastoma, spares healthy brain tissue and more effectively kills cancer cells.

Their study was published in Nature Communications​.

The work is in the preclinical phase, but the authors say it reveals the potential for a lifesaving treatment of children and adults with solid tumors.

Dr Shahab Asgharzadeh, a physician scientist at the Cancer and Blood Disease Institute of CHLA, said that CAR T therapy works in leukemia by targeting a unique protein, or antigen, on the surface of leukemia cells. “When the treatment is given, leukemia cells are killed. CAR T turns the patient's immune system into a powerful and targeted cancer-killer in patients with leukemia. This antigen is also on normal B cells in the blood, but this side effect can be treated medically."

On the other hand, solid tumors like breast cancer or neuroblastoma present a dilemma, he said.

Many of the antigens they have on their surface are also found in healthy tissues where toxicity cannot be safely managed, as in leukemia. In patients with solid tumors, treatment with CAR T-cells kills both cancer cells and healthy tissues indiscriminately. Because of this and suppressive immune environment within the solid tumor, preclinical studies that targeted these cancers resulted in little efficacy or unacceptable levels of toxicity.

"CAR T therapy is incredibly powerful, but for solid tumors it has significant barriers,"​ said Dr Babak Moghimi, the lead author. "We needed a way to boost the CAR T-cells to make them fight harder and smarter against the cancer. But we also want to save brain cells and other healthy tissue."

The team, therefore, set about evaluating a new CAR T technology called synthetic Notch (or synNotch). SynNotch CAR T-cells have a unique property - called gating - that allows them to target specific cancers very precisely.  

Dr Moghimi said the synNotch protein on the surface of the T-cell is designed to recognize the antigen GD2. When it does, the synNotch protein instructs the T-cell to activate its CAR T properties, enabling its ability to recognize a second antigen, B7H3. The T-cell has to follow these specific instructions, which means it can only kill cells with both antigens.

This gating property is key to minimizing toxicity, said the team. Healthy cells will sometimes have low levels of one of the antigens, but not both. Solid tumors like neuroblastoma have both GD2 and B7H3 antigens, which Dr Asgharzadeh's team has engineered the synNotch cells to recognize.

The team was also able to surmount another challenge. "With normal CAR T therapy, the CAR T-cells burn out and are no longer active after some time. But we discovered the synNotch CAR T-cells are more metabolically stable because they are not activated constantly,"​ said Dr Asgharzadeh.

This means they use less energy, which allows them to continue to fight the cancer for a longer period of time, he explained.

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