BioPharma, Pharma

Experts at BIO, ASCO weigh in on CAR-Ts versus bispecific antibodies

CAR-Ts have generated excitement, but bispecific monoclonal antibodies may continue to have a competitive edge in some cases.

CAR-T therapy has been getting a lot of attention from drugmakers, investors and clinicians in recent years, but there’s also a battle raging between it and another form of therapy going for the same targets.

A quick refresher here. CAR-T therapy involves extracting patients’ T cells, using genetically engineered viruses to make them attack cancer cell-surface proteins called antigens, and reinfusing them into the body. With two of the therapies now on the market – Novartis’ Kymriah and Gilead Sciences’ Yescarta – and bluebird bio’s bb2121 already in a registration-directed clinical trial, nobody can deny that CAR-Ts have come into their own, even with their dangerous and potentially fatal side effects.

Yet, a parallel trend in oncology drug development has also complicated CAR-Ts’ place in cancer therapy, namely bispecific monoclonal antibodies, particularly those that target the same antigens as their CAR-T counterparts. At the ongoing BIO meeting in Boston and the recently-concluded ASCO meeting in Chicago, several experts weighed in on where the respective therapeutic modalities stand.

From a regulatory standpoint, CAR-Ts have pulled ahead of bispecifics. Kymriah was approved last year for relapsed and refractory acute lymphoblastic leukemia (ALL) in children, while Yescarta was approved shortly thereafter for diffuse large B-cell lymphoma (DLBCL) in adults, followed by Kymriah’s DLBCL approval earlier this year. Meanwhile, only one bispecific antibody is on the market, Amgen’s Blincyto (blinatumomab). While initially approved in 2014, Blincyto – which, like Kymriah and Yescarta, targets the CD19 antigen – is only for relapsed/refractory ALL in children and adults, not DLBCL.

The other high-profile CAR-T company, bluebird bio, is targeting BCMA, an antigen widely expressed in multiple myeloma. Bluebird’s partner in the effort, Celgene, is developing a bispecific antibody and an antibody-drug conjugate targeting BCMA, as is British drugmaker GlaxoSmithKline.

Celgene’s head of global hematology and oncology marketing, Wim Souverijns, said at the ASCO meeting that there is likely room for sequential treatment with bispecifics and CAR-Ts with the same antigen targets. A potential proof of concept for that, he said, is an analysis Gilead presented at ASCO from ZUMA-3, its trial of Yescarta in adult ALL patients. The analysis showed that patients who had received Blincyto and whose cancer continued to express CD19 responded to subsequent treatment with Yescarta.

Speaking at the BIO meeting, Michael Kalos, vice president for immunooncology and oncology cellular therapies at Johnson & Johnson’s Janssen division, agreed, adding that bispecifics’ greater ease of manufacturing relative to CAR-Ts made it possible for them to have an advantage in earlier stages of a disease. Janssen plans to start enrolling patients in a Phase Ib/II study of its own BCMA-targeting CAR-T, licensed from a Chinese firm, later this year.

In fact, it’s CAR-Ts’ cumbersome manufacturing process that could hinder their popularity, particularly in adult ALL, said Mark Levis, who heads the leukemia program at Johns Hopkins University, at the ASCO meeting. Blincyto’s off-the-shelf advantage relative to CAR-T has made it a more widely used therapy option for relapsed and refractory ALL than CAR-T cells, he said. Another hurdle is that while CAR-Ts may have somewhat better efficacy than Blincyto, they are not curative because patients must still receive subsequent stem cell transplant, which raises the question of why patients should not simply receive Blincyto followed by transplant, he said.

Indeed, the figures that have emerged from Novartis and Gilead since their therapies’ approval would seem to support Levis’ experience regarding CAR-Ts’ popularity, or lack thereof. In December, Bloomberg reported that since Yescarta’s approval for DLBCL two months before, only five patients at the 15 cancer centers offering it had actually received it, with doctors blaming the difficulty in getting Medicare, Medicaid and private insurers to pay for it. Meanwhile, in April, Novartis reported in its first-quarter earnings that Kymriah – with a list price of $475,000 per treatment – had sales of $12 million. Evaluate Pharma had forecast 2018 sales of $134 million for Kymriah and $305 million for Yescarta. Blincyto’s 2017 sales were $175 million.

The difference between bispecific antibodies and CAR-T is that one is a therapy in a bottle, while the other is a “customized immune therapy that’s a fancy stem-cell transplant,” said Bassil Dahiyat, CEO of Los Angeles-based Xencor, which specializes in developing bispecific antibodies. There will likely be competition between the two modalities given that cancer treatment is about multiple lines of therapy, he said, citing the example of Roche’s CD20-targeting monoclonal antibody Rituxan being used in multiple lines of lymphoma treatment. Bispecifics, he said, have the advantage of feasibility and scalability. One of Xencor’s therapies, XmAb14045, targets CD123 in acute myeloid leukemia and related leukemic diseases, which is also the target of UCART123 in the same indications, developed by French drugmaker Cellectis. However, UCART123 is an allogeneic “off-the-shelf” CAR-T, meaning it does not depend on using patients’ own cells for manufacturing.

Photo: Alaric DeArment, MedCity News