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10 Years of CAR-T – The Top 10 Milestones

Anna Osborne
3 May 2022
In this blog, I look back over the past 10 years of CAR-T and highlight some of the key milestones during this advanced therapy’s incredible progression.

May 2022 marks the month 17-year-old Emily Whitehead, the first pediatric patient in the world to receive CAR-T cell therapy, celebrates a momentous milestone: 10 years’ cancer free.

Not only is this a meaningful occasion for Emily and her family, who received Emily’s devastating diagnosis of acute lymphoblastic leukaemia when she was just 5 years old, but it is also a significant historical moment in science, and more specifically, advanced therapies, as cementing advanced therapies’ place at the forefront in finding a cure for cancer.

As Emily reaches this pivotal milestone, I have taken a look back at the notable advances CAR-T has made over this instrumental period of time, which saw CAR-T go from an investigational product on the sidelines, to a more viable aspect in the treatment of many indications of cancer.

  1. The First Pediatric Patient Receives CAR-T

It was April 2012 when Emily became the first pediatric patient to receive an experimental and novel CAR-T cell therapy. Following two relapses and with all standard treatments exhausted, she was enrolled in a Phase I clinical trial evaluating the CAR-T drug, Kymriah, as a treatment for relapsed/refractory acute lymphoblastic leukaemia in pediatric and young adult patients. Her T cells were extracted and genetically engineered with CARs. These cancer cell targeting CAR-T cells were then infused back into her blood. Emily was confirmed to be cancer-free in May 2012, and has remained in remission ever since.

  1. The FDA Grants CAR-T a ‘Breakthrough Therapy’

In July 2014, Novartis became the first pharmaceutical company to be granted breakthrough therapy status by the FDA for a CAR-T cell therapy. Novartis’ CTL019 was the most developmentally advanced CAR-T of its time. Early–phase clinical data had shown positive results for CTL019 as a treatment for relapsed/refractory acute lymphoblastic leukaemia in both adult and pediatric patients. Gaining this new status increased interaction with the FDA in the aim of accelerating the clinical development and review of this drug in the processes of commercialization.

This grant was a huge moment in the world of CAR-T. Arguably, this was the FDA showing their support and understanding of the potential of CAR-T treatments for the first time, and their willingness to put time and effort into their development. Consequently, the world took note of the life-saving potential of these little-known therapies.

  1. Development Begins for CAR-T to Combat Solid Tumors

All successes in CAR-T in its early days were seen in liquid tumors. Solid tumors appeared to present unique difficulties and less susceptibility to CAR-T therapies. Solid tumors cause many additional obstacles including challenges in reaching the tumor site and a hostile tumor microenvironment.

In 2014 results were published outlining a novel approach to targeting solid malignancies using mesothelin-directed CAR-Ts. Mesothelin is a tumor-associated antigen expressed on the surface of a wide range and high percentage of solid tumors. Preclinical results of mesothelin-CAR-T delivered systemically and regionally demonstrated anti-tumour effects against solid tumors.

Despite progress since this first discovery, work to produce a successful CAR-T for solid tumors is still on-going.

  1. First CRISPR CAR-Ts Built

In 2017 evidence of a novel approach using the gene editing tool, CRISPR/Cas9, devised by researchers to introduce CAR genes into T cells in place of the standard retroviral vector method of delivery, was reported. This new delivery method allowed for CAR genes to be entered at a specific locus – the T cell receptor alpha-chain constant (TRAC) –  in the T cells. Preclinical studies showed that CAR-T cells genetically engineered in this way were more potent and demonstrated uniform expression.

CRISPR/Cas9 produced CAR-T cells aimed to increase on-target T cell editing, lower patient dose due to higher potency and enable faster and cheaper manufacturing.

  1. The FDA Approves the First Two CAR-Ts: Kymriah and Yescarta

2017 was a landmark year for CAR-T as the first two therapies crossed the regulatory finish line. The FDA was the first regulatory body to recognize and award the potential of CAR-T, allowing their life-saving effects to be more accessible to patients.

The FDA approved Novartis’ Kymriah for the treatment of relapsed/refractory acute lymphoblastic leukaemia in pediatric and young adult patients. This approval was based upon the ELIANA clinical study which demonstrated a high level of safety and efficacy in participating patients. Of the 63 patients receiving infusion of Kymriah, 83% achieved completed remission with or without incomplete blood count recovery.

The second CAR-T to be approved by the FDA was Kite’s Yescarta for the treatment of adult patients of relapsed/refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma. Kite’s pivotal ZUMA-1 trial demonstrated an overall response rate of 72%, with 51% of these patients having no detectable cancer remaining. Additionally, there was a 99% manufacturing success rate and a median turn-around time of 17 days.

  1. The EMA Approves Kymriah and Yescarta

Quick to follow in the footsteps of the U.S., 2018 saw the European Medicines Agency approve the same two CAR-T cell therapies recently approved by the FDA, for use in Europe. Novartis’ Kymriah received EMA approval for the treatment of relapsed/refractory acute lymphoblastic leukaemia in paediatric and young adult patients, and diffuse large B-cell lymphoma in adult patients, after two or more previous lines of systemic therapy.

Kite’s Yescarta, was approved by the EMA for the treatment of adult patients of relapsed/refractory large B-cell lymphoma, including diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma, to be given after two or more lines of systemic therapy.

Both approvals come two years after Kymriah and Yescarta were the first medicines under the EMA’s PRIME scheme to receive a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), enhancing their regulatory support.

  1. The FDA Approves Tecartus, Breyanzi, and Abecma

Whilst the world stood still in the midst of a pandemic, 2021 demonstrated that CAR-T had maintained momentum in their clinical development in hematological malignancies and regulatory recognition, with an influx of FDA approval.

To kick things off, Kite’s Tecartus received FDA approval for relapsed or refractory mantel cell lymphoma. Gaining subsequent approval for the additional indication of relapsed/refractory B cell precursor acute lymphoblastic leukaemia later that year.

Next to receive the FDA nod was Juno Theraputics’ (a Global Myers Squibb Company since acquired by Celgene) CAR-T product, Breyanzi, targeting adult patients with r/r large B cell lymphoma including: DLBCL – including DLBCL stemming from indolent lymphoma -, high-grade B cell lymphoma, primary mediastinal large B cell lymphoma and grade 3B follicular lymphoma. Breyanzi will be a treatment option for patients after two or more lines of systemic therapy.

Following in quick succession, the FDA approved the first CAR-T for multiple myeloma – Celgene Corporations’ ABECMA. Patients with relapsed/refractory multiple myeloma eligible for ABECMA will have previously received four or more prior lines of therapy.

  1. The NMPA Approves Carteyva in China

The busy year of CAR-T approvals continued in 2021 as we saw the first approval of a CAR-T by China’s NMPA. JW Theraputics’ Carteyva received NMPA approval for the treatment of adult patients with relapsed or refractory large B cell lymphoma following previous treatment with two or more lines of systemic therapy – the first CAR-T to be independently developed and gain Category 1 biologics product status in China.

This approval came in light of the RELIANCE study – the largest clinical study of a CAR-T of its time in China.  ORR was reported as 77.6%, with a CR of 51.7%, at a median follow up of 17.9 months.

  1. The FDA Approve Carvykti for MM

The first quarter of 2022 has seen big news in CAR-T continuing to come through. The newest CAR-T to be approved by the FDA is Janssen’s Carvykti. It is the second approved CAR-T therapy to treat relapsed or refractory multiple myeloma. Patients to be treated with Carvykti will previously have had four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38.

Janssen and their collaborative partners, Legend Biotech, secured the FDA’s approval for Carvykti following durable clinical responses demonstrated in the pivotal CARTITUDE-1 trial. 98% of relapsed/refractory multiple myeloma patients responded to treatment and 78% experienced a stringent complete response.

  1. CAR-T Patients Mark 10 years in Remission

May 10th 2022 marks 10 years that Emily Whitehead, the first pediatric patient to receive CAR-T for the treatment of her ALL, has been cancer free – a personal and worldwide landmark occasion and cause for great celebration.

Long-term CAR-T success has also been demonstrated in other patients. Earlier this year, Nature published analysis on two patients, Bill Ludwig and Doug Olson, who back in 2010, became the first participants to sign up to an investigational clinical trial for a CAR-T treatment ran by the University of Pennsylvania to combat refractory chronic lymphocytic leukaemia (CLL) after having exhausted treatment options. Both patients achieved remission that same year. A recent publication notes this remission was sustained in both patients for over 10 years after infusion, with CAR-T cells remaining detectable in the longest persistence of CAR-T seen in CLL.

A Note as CAR-T Moves Forward…

It is incredible to look back on the success of CAR-T over the last 10 years. As we start to see the first approvals of these products by regulatory bodies in last five years, more and more patients are able to access life-saving CAR-T therapies and evidence for there potential continues to grow. Research in the already approved indications and CAR-T products,  as well as for many new disease and new variations of CAR-Ts, intends to advance and broaden their success as we head into the future.

Despite the evident success and multiple reasons to be celebrating CAR-T therapies still face multiple obstacles including to ensure continued safety. As we move into the next 10 years, arguably the biggest challenge for CAR-Ts is to replicate the positive results they have seen against hematological malignancies, in solid tumors and other disease areas.

Emily and her parents continue to work tirelessly running the ‘Emily Whitehead Foundation’ to raise awareness of the life-saving effects of CAR-T, as well as raising funds for essential research to ensure that others can experience similar potentially curative treatments and to be celebrating their own 10 years in remission.

If you would like to find out more, donate or purchase a ’10 years of CAR-T’ T-shirt, please click here.