In The News and Answering Your Questions: CART cell therapies for Blood and Marrow cancers
Thursday 8 June 2023
Dr Kirsten Herbert* MBBS(Hons) BSc(Med) FRACP PhD
Consultant Haematologist and Co Director, The Blood Unit at Cabrini Health.
Consultant Haematologist Peter MacCallum Cancer Centre.
We are getting a lot of questions from our patients and their families regarding the announcement this week of Therapeutic Goods Administration (TGA) approval of Carvykti (ciltacabtagene autoleucel. made by Janssen-Cilag) a chimeric antigen receptor T cell therapy for myeloma which is now TGA approved for treatment of people with multiple myeloma whose disease has relapsed after 3 previous lines of other treatments. Read below for answers to some commonly asked questions on this topic from Dr Herbert who is a Haematology Specialist both in The Blood Unit and at Peter MacCallum Cancer Centre and has a special interest in Cellular Therapies for Cancer and other Degenerative Disorders.*
What does “TGA approval” mean? TGA is responsible for reviewing all the data on safety and efficacy and any health claims that are made by the manufacturers of any “therapeutic good” (medicines, technologies, devices, blood products, etc). TGA approval states that there is adequate evidence for the health claims regarding safety, quality and efficacy made for the Therapeutic Good, and the product can then be placed on the Australian Registry of Therapeutic Goods. This does not mean that the product is funded for use within our Health System (see below for further details).
What other CART therapies are approved in Australia? TGA has also approved CAR-T therapies for aggressive B cell lymphoma – Kymriah (tisagenelecleucel, made by Novartis) and Yescarta (axicabtagene ciloleucel – made by Gilead). These CAR-T are approved for treatment of Diffuse Large B cell Lymphoma (DLBCL), Primary Mediastinal B cell Lymphoma (PMBCL), grade 3B Follicular lymphoma (FL), Richter’s transformation of Follicular, Marginal Zone or Lymphoplasmacytic lymphoma, where the disease has relapsed despite at least two prior lines of therapy. Gilead’s Tecartus (brexucabtagene autoleucel) is also approved in Australia for adults with relapsed or refractory Mantle Cell Lymphoma or B cell Acute Lymphoblastic Lymphoma.
What CART therapies are actually publicly funded in Australia? Kymriah and Yescarta have been approved and are now publicly funded for use in relapsed or refractory B cell Acute Lymphoblastic Leukaemia in children and young adults up to age 25 years. Adults with relapsed or refractory DLBCL after two or more lines of systemic therapy can access fully funded Kymriah and Yescarta in Australia.
Where can I access CART therapies in Melbourne? Within Melbourne, publicly funded CAR-T for paediatric B-ALL and relapsed/refractory DLBCL is available at numerous of the large public hospitals. These large Cancer Centres and some other hospitals are also running clinical trials of CAR-T in an experimental capacity. Your TBU Haematologist will discuss the appropriate option with you and refer you to the most ideal place if this is the best option for your cancer care. As funding becomes available for the other approved indications for CAR-T listed above, your Haematologist will include these in the discussions regarding your next best treatment option.
What is a CAR-T therapy? CAR-T are genetically modified T cells that are able to kill cancer cells. These immune cells are collected from the blood stream, and are engineered in a highly specialised Manufacturing Facility to recognise and kill cancer cells. They are either sourced from the patient themselves, or from healthy donors in some situations.
What are the drawbacks of CAR-T therapy? Whilst they are very promising therapies for blood cancers that have proven resistant to conventional treatments, there can be significant side effects of CAR-T therapies. These include Cytokine Release Syndrome (CRS) with fever, very low blood pressure. If severe, CRS can lead to ICU admission and organ failure. There are specific medications which treat CRS and patients often make a full recovery. There is also a neurological toxicity syndrome that can cause confusion, seizures and if severe, coma. Patients being considered for CAR-T therefore need to be carefully selected for their fitness to withstand these toxicities (should they happen) as determined by their age, other comorbidities and performance status. With careful management and improvement in the design of these treatments, we hope to reduce the severity and improve the prevention and treatment of these adverse effects. Longer-term medical issues can include low blood counts and risk of infection which may require treatments for months after the CAR-T therapy. Research is ongoing to determine the psychosocial costs to the patients of such intensive treatments. The other drawback is the cost – these treatments are extremely expensive to develop and manufacture (one treatment can cost about $500,000). The Australian Government is still determining how such treatments can be afforded in our publicly funded health system. Because of the cost, public funding is going to be key to obtaining access to these treatments for Australian patients.
Will CART cell therapy cure my blood cancer? The honest answer is not in everyone, and we don’t yet know how often we will achieve true cures with these therapies. They are currently being used in the most difficult group of diseases which have failed multiple prior lines of therapy, but for example in a CAR-T study of 51 patients with relapse B cell acute lymphoblastic leukaemia, CAR-T cell therapy achieved 83% complete remission (clearance of detectable disease), which is quite remarkable in patients with relapsed disease and no other viable treatment options, and 50% of patients had had no relapse at 6 months, and 50% of patients were still alive at just over 1 year. We have not been following patients long enough to know how many patients achieve true cures, with no disease detected decades after treatment. We also don’t know whether using these treatments earlier in the disease journey (i.e. up-front or after only one line of therapy has failed) will result in better remission and cure rates.
My disease is approved but not yet funded for CAR-T. When will CAR-T therapy be available to me or my loved one? It is important for patients to understand that Approval from TGA is only the first step in obtaining funding for this treatment in Australia. Currently in Australia the only fully funded CAR-T therapies available are Kymriah and Yescarta for Paediatric B-ALL, and adults with relapsed or refractory DLBCL who have failed two or more lines of previous systemic therapy. In the mean time if there is a clinical trial or other option available to you, your TBU Haematologist will discuss it with you.
How will these therapies achieve funding in Australia and can I help? CAR-T cell therapy is being managed as a technology rather than a ‘medicine’ so funding must be sought through the Medicines Services Advisory Committee (MSAC) rather than the Pharmaceutical Benefits Advisory Committee (PBAC) which advises which medicines should be considered for funding on the Pharmaceutical Benefits Scheme (PBS) in Australia. MSAC is an independent committee which advises the Health Minister regarding submissions for new medical technologies, and informs the Minister about the data available for safety, efficacy and cost effectiveness of these new treatments. It is possible for patients and the wider community to provide feedback to the MSAC regarding their own story, and why having these treatments might be important to you or your loved one. Comments can be sent to [email protected].
What other options are there in my relapsed or refractory blood cancer? This is a very exciting time in Haematology Research. The evolution of CAR-T cell therapies is running in parallel with other drugs such as bispecific antibody therapy. Bispecifics (and now trispecifics) aim to achieve the same end as CAR-T cell therapy by forcing T cells to kill cancer cells. Bispecifics currently under investigation include Glofitamab which has been given TGA permission to apply for registration within Australia, and Epcoritamab which has just also achieved provisional TGA approval in Australia for patients with relapsed DBLCL. Our patients may be aware of both these agents (as well as other novel immunotherapies such as the monoclonal antibody Tafacitamab), because we at The Blood Unit at Cabrini have been treating patients on early phase clinical trials of these agents. Other bispecific antibodies are also gaining traction in the blood cancer space. Cabrini and TBU is participating in numerous clinical trials of bispecific antibodies and other immunotherapy agents, and small molecules, for a range of blood cancers. There are many other emerging technologies in Cancer Medicine, and Cabrini and TBU continue to work at the forefront of participating in research into these novel therapies to add to the body of data regarding these agents and to improve access for Australian patients to these drugs, even as we wait for public funding for CAR-T therapies.
Dr Herbert is a Specialist Haematologist and Co Director of The Blood Unit at Cabrini, one of Melbourne’s largest Private Cancer services, and has been a Haematologist at Peter MacCallum Cancer Centre for the last 25 years. She has a PhD in Haematopoietic Stem Cell Mobilization. She also serves as Chief Medical Officer of Cell Therapies P/L and has a long history of working and advising in the research and development space for novel cellular therapies for the treatment of cancer at Peter Mac, CTPL, and previously at the Australian Stem Cell Centre, Stem Cell Australia and as part of a large Collaborative Research Centre for Cell Therapy Manufacturing.