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CAR-T – The Driving Force Behind a Cure for Blood Cancer?

Anna Osborne
10 May 2022
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To date, all CAR-T cell therapy approvals have been in hematological malignancies.
As we witness the first patients to receive CAR-T for their blood cancers reach the 10-year cancer free milestone, we ask, what has led to success for this specific indication, how will this one-time therapy change how we address cancer treatment and can we now justifiably label CAR-T as a cure for blood cancer?

Hematology in the CAR-T Driving Seat

Due to its immunotherapeutic nature, CAR-T is inherently an oncological target, destroying proliferated cancer cells that have managed to evade immune destruction and the anti-tumor functions of effector T cells.

The autologous T cells that are extracted and genetically reprogrammed to include the addition of chimeric antigen receptors are infused back into the patient as a one-time treatment and attach to specific tumor cell surface antigens, initiating an anti-tumor pathway killing these cells.

Current approved CAR-Ts target either CD19 or B cell maturation antigen (BMCA) B cell antigens [1] .

So far seven CAR-T products have been approved: six by the FDA – Kymriah, Yescarta, Breyanzi, Tecartus, Carvykti and Abecma, two by the EMA – Kymriah and Yescarta, and one by the NMPA – Carteyva (See Figure 1).

Collectively these CAR-T approvals cover eight different categories of hematological malignancies, including: one indication of leukemia, five indications of lymphoma and two indications of multiple myeloma.

Following the first CAR-T approval – Kymriah for acute lymphoblastic leukemia by the FDA in 2017 – subsequent approvals saw success turn to lymphoma targeted therapies, with a total of 14 approvals taking place across the multitude of lymphomas.

Most recently, two CAR-Ts have been approved for the treatment of relapsed or refectory multiple myeloma (r/r mm) by the FDA; Abecma in March 2021 and new kid on the block, Carvykti, in February 2022 [2].

Figure 1. CAR-T Products and the Indications They Are Approved for

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Clinical Evidence Fuelling a Cure

Looking at some of the most up-to-date CAR-T clinical evidence it is clear to see the years of intricate research and development paying off with promising effects in patients of hematological cancers.

As mentioned, pediatric acute lymphoblastic leukemia was the first indication to be approved for CAR-T treatment, with the focus of much initial CAR-T research targeted this indication. May 2022 will see the first ever patient to receive CAR-T for their acute lymphoblastic leukemia celebrate 10 years in remission [3]. Results from this first global CAR-T clinical trial, ELIANA, demonstrated an overall remission rate of 81% at a median follow-up of 13.1 months of the 75 trial patient population, with Kymriah detectable in the blood at 20 months [4].

These positive initial results and promising long-term effects made the world sit up and pay attention to CAR-T, arguably acting as a catalyst to the influx of subsequent clinical focus in hematological malignancies.

Kite’s Yescarta for adult relapsed or refractory is the latest CAR-T to gain the FDA’s seal of approval – the first treatment to improve current standards of care in 30 years. Kite’s ZUMA-7 Phase III clinical trial reported an event-free survival of 8.3 months, compared to the 2 months observed in previous treatment plans. Of the 42.6% of trial patient population alive 5 years post one-off treatment, 92% had needed no further treatments [5].

Similarly, Janssen’s Carvykti for the treatment of adults with relapsed or refractory multiple myeloma achieved approval in the U.S. this year in response to impressive data from the ongoing Phase I/II CARTITUDE-1 study. Durable responses were recorded at an 18-month follow-up, with 98% of patients responding to the therapy and 78% experiencing a stringent complete response [6].

Patients Steering the Need for a Cure

According to documentation published by the American Cancer Society 2022, over 1.9 million people will be diagnosed with cancer in the U.S. in 2022 [7].

It Is estimated that 2022 will see a nearly 190,000 combined new cases of hematological cancer in the U.S. and a predicted 21,170 deaths from lymphoma, 12,640 from myeloma, and 24,000 from leukemia.

It is estimated in the U.S. that leukemia will be the 6th highest cause of cancer death in males and 8th in females. With non-Hodgkin lymphoma the 9th highest cause of cancer death in both males and females.

In the age category 0–40, data recorded between 2016–2018 identified that the probability of developing leukaemia in the U.S. was 1 in every 386 people and 1 in every 498 people in males and females respectively. The same data revealed the chance of developing non-Hodgkin lymphoma was 1 in 343 and 1 in 453 in the age range 0–59 in males and females respectively [7].

In the UK, blood cancer is the third biggest cause of cancer death, according to Blood Cancer UK. The overall average 5-year survival rate for the collective types of lymphoma, leukemia and myeloma is 70%. However, some indications, including myeloma, are as low as 50%.

Current standards of care see the use of: chemotherapy, radiotherapy, proteasome inhibitors, immunomodulatory drugs, steroids, antibodies and BMCA- targeting drugs, as leading treatments. Many blood cancer patients are relapsed or refractory. At every relapse a new therapeutic approach is implemented as a treatment plan [8].

The majority of CAR-T drugs so far are approved to be used as third, fourth or even fifth lines of treatment. Kite’s recent approval of Yescarta for relapsed or refractory large B cell lymphoma is to be used as a second line therapy.

Warner Biddle, SVP, Worldwide Cell Therapy Commercial at Kite, a Gilead Company told Phacilitate in a recent interview that, “Back in 2017 Kite was approved for Large B cell lymphoma in the third line setting. This new indication approved by the FDA actually expands usage into the second line setting, which means that more patients can get access to therapy. In fact, we are effectively doubling the eligible patients who can get access to Yescarta. It also means patients can get access to these therapies earlier, which means they may have better outcomes.”

Click here to watch the full video.

Gearing up Clinical Developments

All but a handful of the current 1000+ CAR-T products in pre-clinical, Phase I, II, III and pre-registration development are cancer treatments. 146 of these oncological indications under CAR-T investigation are hematological malignancies (See Figure 2) [2].

Leading in CAR-T involvement are diffuse large B-cell lymphoma and B-cell acute lymphoblastic leukemia, featuring in 129 and 128 pre-clinical and clinical trials respectively.

A number of investigational activities for CAR-T in different indications of lymphoma, including: follicular lymphoma, non-Hodgkin lymphoma and mantel cell lymphoma, are also in progress.

There is also a substantial amount of development underway for both relapsed and refractory multiple myeloma – a blood cancer only to see CAR-T success in recent years.

Despite therapeutic advances, multiple myeloma remains largely incurable. The majority of multiple myeloma patients are relapsed or refractory. According to the National Cancer Institute, although data from the approval determining clinical trial for Abecma shrank myeloma tumors in 72% of the trial population, these results only lasted for an average of 11 months [9]. Further exploration of CAR-T in multiple myeloma is required if we are to replicate the sustained successes we are seeing in CAR-T-treated leukaemias and lymphomas .

According to Global Data, there are currently six CAR-T drugs in the pre-registration stages having completed the necessary clinical trials and awaiting registration or approval, and 13 CAR-T trials in Phase III – all of which are hematologically targeted (see Figure 3) [2].

A few of these products in pre-registration include: Legend Biotech’s Carvykti for the treatment of relapsed and refractory multiple myeloma in both the EU and Japan, and, Bristol-Myers Squibb’s Breyanzi for diffused large B cell lymphoma in the U.S. as well as Canada, Japan and Switzerland and for follicular lymphoma in Canada and Switzerland.

This level of attention CAR-T is receiving in the developmental stages is promising. It appears as if we are to witness a high level of new CAR-T products marketed for further hematological malignancies in the near future.

Figure 2. The Number of Developmental CAR-T Clinical Trials Currently Taking Place for Different Hematological Oncological Drug Indications

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Figure 3.  CAR-T Products Currently in Phase III and Pre-Registration

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On Track to Finding a Cure?

The milestone of patients treated with one-time CAR-T cell therapies for their haematological cancers celebrating 10-years in cancer remission brings with it a big question: Are we ready to call CAR-T a blood cancer cure?

It is clear that we are heading in the right direction. CAR-T is now considered an effective modern cancer medicine, allowing many patients of lymphoma, leukemia and myeloma to achieve remission.

The number of recent CAR-T product approvals and products in the pipeline targeting hematological malignancies are a reflection on the clinical successes in these indications.

However, there is still a long way to go. There are issues surrounding safety and efficacy, including: off-target effects, therapeutic resistance, and, toxicity- most notably cytotoxicity and neurotoxicity (10).

Another critical issue holding back CAR-T progress is patient access. In England, only a small number of centers offer the specialist treatment – currently only eight centres for adults and nine for children (11).

In a recent interview with Phacilitate, Michael Bishop MD, Director of Cellular Therapy at The University of Chicago, commented that: “I think it’s the most disappointing aspect that I see in this is that we are estimating just for lymphoma patients that maybe only a fifth of patients who could potentially benefit from that potentially life-saving [CAR-T] treatment are actually receiving it.”

If more patients accessed CAR-T as a treatment for their blood cancer, and in the earlier stage of the disease, it would build a clearer picture of the therapy’s curative potential, advance the identification of areas for development and provide greater evidence for accelerating approvals.

In the timeline of cancer treatment, CAR-T is still in its early phases and much development is still vital. However, it isn’t too adventurous to be tentatively optimistic that one day soon we will be labelling CAR-T a ‘blood cancer cure’.

To view Figures 1-3 click here 

References:

  1. Blood Cancer UK. 2022. Blood Cancer UK | What is CAR-T therapy?. [online] Available at: <https://bloodcancer.org.uk/understanding-blood-cancer/treatment/what-is-car-t-therapy/> [Accessed 9 May 2022].
  2. com. 2022. ShieldSquare Captcha. [online] Available at: <https://www.globaldata.com/what-we-offer/globaldata-explorer/> [Accessed 9 May 2022].
  3. Emily Whitehead Foundation. 2022. Our Journey | Emily Whitehead Foundation. [online] Available at: <https://emilywhiteheadfoundation.org/our-journey/> [Accessed 9 May 2022].
  4. 2018. Novartis announces NEJM publication of updated analysis from ELIANA trial showing longer-term durable remissions with Kymriah(TM) in children, young adults with r/r ALL. [online] Available at: <https://www.novartis.com/news/media-releases/novartis-announces-nejm-publication-updated-analysis-from-eliana-trial-showing-longer-term-durable-remissions-kymriahtm-children-young-adults-rr-all> [Accessed 9 May 2022].
  5. Kite, A Gilead Company, 2022. Yescarta® receives u.s. fda approval as first car t-cell therapy for initial treatment of relapsed or refractory large b-cell lymphoma (lbcl). [online] Available at: <https://www.kitepharma.com/news/press-releases/2022/4/yescarta-receives-us-fda-approval-as-first-car-tcell-therapy-for-initial-treatment-of-relapsed-or-refractory-large-bcell-lymphoma-lbcl> [Accessed 9 May 2022].
  6. 2022. U.S. FDA Approves CARVYKTI™ (ciltacabtagene autoleucel), Janssen’s First Cell Therapy, a BCMA-Directed CAR-T Immunotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. [online] Available at: <https://www.janssen.com/us-fda-approves-carvykti-ciltacabtagene-autoleucel-janssens-first-cell-therapy-bcma-directed-car-t> [Accessed 9 May 2022].
  7. Cancer Facts & Figures 2022. [ebook] Atlanta: American Cancer Society. Available at: <https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf> [Accessed 9 May 2022].
  8. Blood Cancer UK. 2019. Blood Cancer UK | Facts and information about blood cancer. [online] Available at: <https://bloodcancer.org.uk/news/blood-cancer-facts/#:~:text=Overall%2C%20the%20five%2Dyear%20survival,who%20doesn’t%20have%20cancer> [Accessed 9 May 2022].
  9. National Cancer Institute. 2021. CAR T-Cell Therapy Approved for Multiple Myeloma. [online] Available at: <https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-ide-cel-car-t-multiple-myeloma> [Accessed 9 May 2022]
  10. Teoh, P. and Chng, W., 2021. CAR T-cell therapy in multiple myeloma: more room for improvement. Blood Cancer Journal, 11(4).
  11. org. 2021. CAR T-cell therapy | Cancer Research UK. [online] Available at: <https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/CAR-T-cell-therapy> [Accessed 9 May 2022].