2944_SM_CART_First_Blog (1)Robert Rovner co-wrote this blog post with Sharon Karlsberg. This article originally appeared in the January 2019 issue of OBR Green.

The “first-mover advantage” is something we’ve come to expect in the commercial world. The first to innovate and come to market usually reaps the greatest rewards, right? Facebook, Uber and Google improved on technology brought to market by actual first-movers MySpace, Sidecar and AltaVista, but then transcended them by addressing their weaknesses.

In the oncology world, we’ve ascribed similar benefits to first-to-market products with a novel mechanism of action, such as Ibrance (palbociclib), Imbruvica (ibrutinib), Keytruda (pembrolizumab) and Opdivo (nivolumab). But as we’ve seen in the high-tech world, a truly disruptive product often presents a significant opportunity for “second movers.” The chimeric antigen receptor (CAR) T-cell therapy market had two breakthrough first movers approved in 2017: Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel). Will their first-to-market advantage sustain long-term growth? Or when we think of CAR-Ts in two to three years, will we look at these as the MySpace of the oncology therapy world?

At the 2018 American Society of Hematology (ASH) Annual Meeting, there were a few updates to inspire confidence in the first-mover CAR-T cohort. For example, a multicenter retrospective study that evaluated the efficacy and safety of Yescarta in a real-world setting for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) found similar complete response (CR), overall response rates and toxicity rates to its registrational trial, ZUMA-1. Novartis also presented longer-term data from one of its pivotal trials, JULIET, evaluating Kymriah in heavily pretreated DLBCL patients, which continued to demonstrate strong durable responses.

These products undoubtedly represent a significant breakthrough in cancer treatment; however, lengthy turnaround times and significant toxicities like cytokine release syndrome (CRS) and neurotoxicity remain barriers to widespread and strong commercial adoption. These weaknesses beg the question: Is there a window of opportunity for second-generation CAR-T platforms to challenge the presumed first-mover advantage of Kymriah and Yescarta? At ASH, we saw evidence of companies making progress towards shorter—almost immediate—turnaround times and fewer instances of severe toxicity that may spur broader uptake of this paradigm-shifting approach to cancer therapy.

Off-the-Shelf CAR-T Solutions

A major contributor to the lengthy turnaround times of the commercially available CAR-T products is that manufacturing is individualized for the patient. Additionally, because the patient’s T-cells are extracted in one location and their CAR-T cells are manufactured in another, this approach is riddled with logistical hurdles requiring costly and time-intensive levels of tracking and coordination between the manufacturing facility, hospital, physician and logistics providers.

Through partnerships with Servier and Cellectis, Allogene Therapeutics, led by former executives of Kite Pharma, aims to address this pitfall with its allogeneic—or “off-the-shelf”—CAR-T cells (UCART). Rather than individualizing CAR-T treatment for the patient, the UCART platform creates engineered T-cells from a healthy donor for use in multiple patients. Theoretically, this could significantly reduce the manufacturing and logistical complexities faced by Kymriah and Yescarta, and “represents the next transformative step in medicine, as it will potentially allow patients all over the world to quickly receive these potentially life-saving therapies in the most efficient and cost-effective way possible,” said Dr. André Choulika, Cellectis’ chairman and CEO, in a company press release. However, will this new approach achieve similar clinical results to existing CAR-T products?

So far, early results are promising. Phase 1 data presented at ASH on UCART19 in R/R acute lymphoblastic leukemia (ALL) showed that 88% of evaluable patients achieved a CR, and no severe neurotoxicity was observed. In contrast, Kymriah achieved an 83% CR rate in a similarly pretreated ALL population, with a 49% incidence of Grade 3 or higher CRS.

Yet Allogene isn’t alone in this off-the-shelf approach. Fate Therapeutics, which is in pre-clinical pursuit with its lead candidate FT819, presented potentially IND-enabling data at ASH. If these off-the-shelf CAR-T platforms continue to show enhanced simplicity with potentially preferable clinical profiles, they may be enough to not only supplant existing CAR-T options but also dramatically expand commercial adoption of CAR-T.

Point-of-Care CAR-T Solutions

Off-the-shelf CAR-Ts are a promising approach to expediting treatment delivery, but they’re only one potential solution. Other manufacturers are preserving the autologous route to CAR-T treatment that Kymriah and Yescarta established, but rather than sending a patient’s own apheresed T-cells to a distant manufacturing facility for reprogramming, they’re bringing CAR-T manufacturing capabilities to the hospital.

Lentigen (a subsidiary of Miltenyi Biotec) is pursuing this point-of-care solution to CAR-T cell production with its CliniMACS Prodigy device, a compact tabletop device that allows for automated production of CAR-T cells within the hospital. This method may obviate the complex and costly delivery process plaguing current CAR-T products. Feasibility and reliability of this production method, however, remain unproven.

Early evidence at ASH shed some light on the promise of this point-of-care production method. In a Phase 1 clinical trial evaluating feasibility and safety of locally manufactured CAR-T cells with the CliniMACS Prodigy in R/R non-Hodgkin lymphoma patients, CAR-T cells were successfully generated for all patients and no production failures were observed. Although CAR-T production using the CliniMACS Prodigy was set for a 14-day turnaround time in the trial, a sufficient number of CAR-T cells were available for infusion within eight days; future trials will likely evaluate shorter manufacturing timelines. With an eight-day turnaround time, the CliniMACS Prodigy device could reduce current CAR-T production timelines up to almost 65% while still allowing Lentigen to capitalize on growing physician comfort with an autologous CAR-T approach established by the first movers.

Going Non-Viral to Improve CAR-T Safety

Reducing logistical complexities and lengthy turnaround times will alleviate some commercial constraints preventing broader uptake of CAR-T, but it’s only one piece of the puzzle. Severe toxicity events like CRS and neurotoxicity have been major concerns with first-generation CAR-T products, as rates of Grade ≥3 CRS can be as high as 23% for Kymriah and 13% for Yescarta, respectively, in R/R DLBCL.

Some manufacturers seek to reduce the frequency of these significant toxicities as another way to differentiate their products. If a CAR-T’s risk profile can be improved, it may even help move these therapies into earlier lines of treatment. Poseida Therapeutics is pursuing this opportunity with its novel autologous CAR-T product in multiple myeloma, P-BCMA-101.

What makes P-BCMA-101 unique is its two-pronged approach to combating CAR-T toxicities. First, P-BCMA-101 is manufactured using a non-viral piggyBac DNA modification platform, which reduces the risk of oncogenesis and mutagenesis relative to viral-based delivery systems used by existing CAR-T products. Second, the platform also allows for the delivery of larger transgenes to T-cells, including a safety switch that reduces or eliminates P-BCMA-101 during treatment in severe instances of toxicity.

At this year’s ASH, Dr. Gregory and his team presented data from a Phase 1 trial evaluating P-BCMA-101 in R/R multiple myeloma patients, which, in addition to showing a 100% ORR in patients receiving the planned Phase 2 dose, showed no evidence of severe CRS (Grade ≥3), and only one patient with low-grade (Grade 2) CRS. Additionally, no patients required safety switch activation, and no instances of neurotoxicity, DLTs or off-target toxicities related to treatment were observed. If P-BCMA-101 continues to show minimal levels of severe toxicity and promising efficacy, a non-viral approach may be the advantage that allows this second mover to expand commercial adoption of CAR-Ts.

Second Mover Benefit? Only Time Will Tell

As we’ve seen with the high-tech industry, disruptive innovation can create many paths to commercial success. At ASH, we saw positive data from:

  • First-generation CAR-T pioneers, who demonstrated sustained clinical benefits of strong efficacy and “manageable toxicity” in expanded real-world populations. The path to success for Kymriah and Yescarta may come from building loyalty and familiarity among the first oncologists to offer CAR-T therapy in their institutions.
  • Second-generation CAR-T improvers, who showed promising early clinical data with faster turnaround times, less toxicity or both. These improvements could expand the number of patients eligible to receive CAR-Ts, creating a larger market for all.
  • Novel CAR-T rivals, such as Amgen’s AMG 420 bispecific T-cell engager (BiTE), which combines an off-the-shelf antibody approach with T-cell engagement to enhance BCMA-specific cell death in R/R multiple myeloma.

Only time will tell whether the second generation of CAR-T therapies will eventually supplant first-generation pioneers. However, with the rapid pace of development in cell therapies, we can be certain that innovations unlocked by up-and-coming CAR-T manufacturers will improve treatment options available to patients across ALL, DLBCL, multiple myeloma and many other malignancies in the years ahead.


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Topics: oncology, oncology manufacturer, CAR-T, American Society of Hematology, pharma manufacturer, pharma commercial model, ASH 2018, first-mover advantage, Kymriah, Yescarta