Liso-Cel

Liso-Cel

The Science

JCAR017, Lisocabtagen maraleucel or Liso-Cel for short is a CAR T-cell therapy currently being developed by Juno Therapeutics, in collaboration with Celgene. The therapy has been granted blockbuster drug status to possibly treat certain patients with aggressive B-cell non-Hodgkin’s lymphoma (NHL).

NHL is a collective name for a group of closely related blood cancers that develop in the lymphatic system. Clear fluid called lymph flows through the lymphatic vessels and contains infection-fighting white blood cells known as lymphocytes. In non-Hodgkin lymphoma, the affected lymphocytes start to multiply in an abnormal way and begin to collect in certain parts of the lymphatic system, such as the lymph nodes (glands).

In B-cell lymphomas, it is B-cells that multiply uncontrollably and loss normal function. B-cells function in the humoral immunity component of the adaptive immune system by secreting antibodies, presenting antigens and secreting cytokines. They are extremely important in fighting infection. 

A CAR-T therapy uses the patient’s own T-cells to fight the cancer. As part of the immune system, T-cells act to identify and destroy abnormal or infected cells. JCAR017 acts to reprogram T-cells to target cells that express a protein called CD19, that is commonly found in B-cell NHL.

To produce JCAR017, a patients T-cells are extracted from the blood and are genetically modified to produce a CAR protein. The CAR consists of an antibody, a protein that interacts with CD19, which can stimulate a signalling domain, sending a message to the T-cell when CD19 binds to it.

JCAR017 aims to provide T killer-cells in a 1:1 ratio with T helper-cells, which in turn activate the bodies own T killer-cells. This should vastly increase the efficiency of the treatment, and reduce the severity and frequency of adverse effects, such as cytokine release syndrome (CRS), common in other CAR-T based therapies.

The Upside 

The therapy is currently focused on aggressive B-cell NHL however trials are secondarily supporting the use in primary mediastinal B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma.

In a Phase I trial called TRANSCEND-NHL-001, patients firstly underwent lymphocyte depletion using fludarabine, a chemotherapy, and cyclophosphamide, an immunosuppressant. JCAR017 was then given intravenously at multiple doses.

Overall response rate (ORR), which refers to a reduction in tumor size over a predefined amount of time, was seen in 80% of patients while complete cancer eradication was found in 55% of patients. Half of patients showed a complete response (CR) after 6 months at a dosing level of 100 million cells.  Preliminary data suggests that the response may be slightly improved with a higher dose of JCAR017, with no increase in toxicity reported so far.

It has to be noted that the median number of lines of prior therapy was 4.5, meaning patients had tried 4-5 prior therapies/treatments with no effect.

Novartis has a similar therapy on the market called Kymriah. This therapy is estimated to cost £282,000 for one course of treatment and Kymriah has been pegged to bring in £150 million in 2019.

The market is relatively small for B-Cell Lymphoma. After a quick search, 6.6 people in 100,000 get diagnosed each year. Say out of 66 million people in the UK, around 4500 people will be diagnosed each year. If all of them were treated with JCAR017 at a similar price to Kymriah, that would mean sales of £1.3 Billion a year. Of course, not all of them would be treated with JCAR017 so lets say a conservative 10% share, that still leaves £130 million a year in sales, about right if you look at the  predicted sales for Kymriah in 2019.

JCAR017 however has more promising efficacy, thus if approved I would argue it may overtake Kymriah.

The Downside

Among 91 patients evaluable for safety, researchers observed cytokine release syndrome in 35% of patients — with one patient developing grade 3 to grade 4 cytokine release syndrome — and neurotoxicity in 19% of patients (grade 3 or grade 4, 12%). Now these numbers are actually quite low, presumably as the therapy progresses through Phase II and III it will be hoped that these numbers stay the same or decrease as more is known about the therapy.

The obvious downside I can see is the cost of the therapy. CAR-T therapies are not cheap at all, after T-Cells have been extracted, modified and reintroduced to the patient a lot of time and a few hundred thousand dollars may have passed. In the UK, the treatment is likely to be rejected funding by the NHS unless it really is a breakthrough therapy. 

Looking at Novartis'  Diffuse Large B-Cell Lymphoma (DLBCL) therapy Kymriah, which the NHS actually struck a deal to fund for children with the condition. The Phase I results for JCAR017 are actually better, a higher percentage of patients were in complete remission at 6 months and the response rate was also slightly higher. 

However, neurologic and CRS adverse events occurred in a far lower percentage of patients in the Kymriah Phase I trial. This does beg some questions about the success of JCAR017 as it moves through Phase II and into Phase II trials. 

The Conclusion

It has been argued that the strong efficacy seen with CAR-T drugs outweigh their costly drawbacks – side effects need intensive treatment, and patients need to be intensively monitored. Some CAR-T therapies have even been granted reimbursement by the Cancer Drugs Fund, which provides interim funding for these drugs until more detailed evidence can show they are cost-effective.

I think this is currently the limiting factor. 

We will have to wait until CAR-T therapy becomes more cost effective. The therapy is still in its early stages and a lot more needs to be known about their impact, price, efficacy, QALY etc before health authorities can commit to spending millions (or billions) on them. 

Nonetheless, JCAR017 is a promising CAR-T therapy with good Phase I results.  Using CD-19 as a target on B-cells has shown extreme promise across all developing cancer treatments, not only Lymphomas. I have high hopes for the therapy going into Phase II/III.

-OC

Disclaimer:
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company who is mentioned in this article. This article is not investment advice, and can't be relied upon by anyone for any reason except, arguably, entertainment purposes. I am not an investment advisor.

https://immuno-oncologynews.com/jcar017/

https://www.nhs.uk/conditions/non-hodgkin-lymphoma/

https://lymphomanewstoday.com/2018/06/01/asco2018-car-t-cell-therapy-jcar017-provides-sustained-anticancer-response-to-aggressive-b-cell-lymphoma-in-trial/
https://www.healio.com/hematology-oncology/lymphoma/news/online/%7Bdfc2e8b3-8601-4343-8e69-bfc093202b7f%7D/lisocabtagene-maraleucel-shows-promise-for-pretreated-non-hodgkin-lymphoma
https://www.businesswire.com/news/home/20181202005055/en/Celgene-Corporation-Announces-Initial-Phase-12-Liso-cel
https://www.novartis.com/news/media-releases/primary-analysis-results-from-novartis-pivotal-juliet-trial-show-kymriahtm-tisagenlecleucel-sustained-complete-responses-six-months-adults-rr-dlbcl-difficult
https://pharmaphorum.com/news/nhs-to-fund-novartis-car-t-therapy-kymriah/
https://www.marketscreener.com/CELGENE-CORPORATION-8736/news/Celgene-Corporation-Announces-Initial-Phase-1-2-Liso-cel-Data-in-Patients-with-Relapsed-Refractory-27707388/
https://seer.cancer.gov/statfacts/html/dlbcl.html