In 2017, Kymriah became the first autologous CAR-T therapy to enter the oncology treatment landscape, treating patients with acute lymphoblastic leukemia (ALL). This approval changed the devastating treatment narrative for patients with hematological malignancies not responding to chemotherapy, bringing new hope for cancer treatment. Since then, the FDA have approved five more auto CAR-Ts for various liquid tumors, including diffused large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantel Cell Lymphoma (MCL), and Multiple Myeloma (MM). 

Most importantly, these groundbreaking treatments are swiftly moving down the treatment line, with Kite’s Yescarta and BMS’ Breyanzi having been recently approved for 2L DLBCL, therefore becoming a tangible reality for a much larger patient population.

However, the promise ofCAR-Ts comes with significant challenges, including lengthy manufacturing Turn-Around-Time (TAT), a frustratingly high rate of relapse due to antigen escape, and last but not least, hefty price tags. To address these challenges, biopharmaceutical companies are developing the “next-gen” CAR-Ts.

Better, Faster, Stronger…CAR-Ts

In an ideal world, CAR-T manufacturers would try to address all challenges associated with this therapy, but the reality is, is that no company has the capacity to focus on everything – developing “next-gen” CAR-Ts implies having to make a strategic choice of which therapy aspects to prioritize, hoping that this will translate into improved outcomes. 

Novartis is currently focusing on enhancing the TAT for its “next-gen” assets YTB323 and PHE885, by utilizing its proprietary T-Charge rapid automated closed manufacturing system. The latter has reduced core manufacturing time to <2 days, whilst also integrating in vivo cell expansion to decrease the overall vein-to-vein time. Other companies are hoping to go even further, by manufacturing the product right where the patient is being treated. This is the vision of CellPoint (recently acquired by Galapagos) which has developed a point-of-care platform with the potential for a 7-day overall vein-to-vein time, by circumventing the current centralized manufacturing approach and thus escaping the complex logistics responsible for the long wait times.

While the development of rapid manufacturing platforms could help improve the outcome of CAR-T therapies by ensuring faster delivery of the product to the patients, other companies are focusing on other aforementioned challenges, such as addressing therapy relapse. This is being explored with dual targeting CAR-Ts that can target two antigens to overcome a potential antigen escape. For instance, Autolus and Miltenyi Biomedicine are currently developing CAR-Ts targeting both CD19 and CD22 for the treatment of ALL, with the aim to overcome the high rate of relapse due to CD19 escape. 

Finally, when discussing next-gen CAR-Ts it is inevitable to mention the rise of allogeneic CAR-T therapy. These consist of CAR-Ts developed from healthy T-Cell donors or iPSCs, as opposed to the patient’s own T-cells (autologous CAR-Ts). In simple terms, allogeneic CAR-Ts are “off-the-shelf” products rather than personalized products, and therefore confer better economies of scale, consistent quality across batches, and reduced dependence on individual patient T-cells fitness. These attractive attributes have led to a notable growth of allogeneic CAR-Ts under development, fueled by large deals and partnerships. One such example is Roche’s recent agreement with Poseida Therapeutics to receive exclusive rights to develop and commercialize the allogeneic CAR-T programs in Poseida’s portfolio. Impressively, this agreement follows last year’s $3.25 billion partnership with Adaptimmune to develop iPSC-obtained allogeneic CAR-Ts, showcasing Roche’s aggressive pursuit to enter and dominate the CAR-T space with the allogeneic approach. 

Companies have focused on different “upgrades” to improve CAR-T therapy, but who will come on top? Will these “next-gen” CAR-T survive the test of time? Or will new MoA upstage CAR-Ts?

Bispecific Antibodies are around the corner 

As if the above-mentioned technological advances in CAR-T are not exciting enough, the pharmaceutical industry is exploring other new MoAs to harness the power of immunotherapy, by engaging endogenous T-cells via bispecific antibodies. Despite entering the market later than CAR-Ts, bispecifics are slowly but surely establishing themselves in the oncology landscape, with notable regulatory milestones occurring this year such as Roche’s Lunsumio conditional EU approval and the expected filing for Genmab/Abbvie’s Epcortimab and Regeneron’s Odronextamab in the coming months.

So far, bispecifics boast promising tumor responses and safety profiles. For instance, Lunsimio demonstrated an ORR of 80%, with a CRR of 60% in patients with r/r FL, while Epcortimab demonstrated a 69% ORR and a 42% CRR in CAR-T naïve patients with r/r LBCL. However, while the safety and efficacy profile remain paramount priorities for HCP and patients, other characteristics of bispecifics may help upstage this therapy over CAR-Ts. More specifically, bispecifics have a convenient edge over autologous CAR-Ts given their “off-the-shelf” nature, allowing for greater manufacturing scalability, lower logistical complexities, and therefore anticipated more affordable prices. 

Who will dominate?

Though it is premature to predict which of these technological advances will dominate the future oncology market, one thing is sure – the competition is fierce. On this note, research describes the development landscape as “oversaturated” with over 800 cell therapies in development for just five blood cancers (ALL, B-nHL, AML MM and CLL). 

With the ever-quickening pace of cell therapy improvements, more than ever, it is essential for CAR-T manufacturers to actively monitor the pipeline activity of competitors and the scientific developments in the wider landscape. This is a simple, yet effective tool for companies to understand how to competitively position their own assets and/or identify technologies to invest in, in order to complement and de-risk their portfolio. Will CAR-Ts live on as the pioneers of novel next-gen technology, or will alternative MoAs derail the billions invested in CAR-T therapy?