Topics-in-Focus is a new EHA program that aims to raise awareness, provide education, stimulate further research and build a network of experts high-impact hematology issues. One of the topics chosen for 2018-2019 is immunotherapy with a focus on CAR-T.
The kick-off session for this project was held at the 23rd Congress of EHA in Stockholm, on June 15.
As part of the launch, a session on chimeric antigen receptor (CAR) T cell therapies, graced by three experts, was held.
CAR-T cell design involves recombinant receptors with antigen-binding and T cell activating function. CAR-T cells can be autologous or allogeneic and once engineered (usually with aid of a viral vector), act as a ‘living drug’. Professor Emma Morris (University College London) focused her presentation on CD19 targeted CAR-T cells in ALL and DLBCL.
“Clinical responses seen in relapsing/refractory (R/R) DLBCL are 40-50% CR, in pediatric ALL 50-80% CR and in adult ALL 70-80% CR, but neurotoxicity and cytokine release syndrome (CRS) are significant," she said. She added that a CD19 CAR with more physiological binding kinetics (CAT-CAR) might improve persistence and reduce toxicity. It is also important to know the functional and differentiation status of the T cells. “Growing evidence indicates that better responses are obtained using T cells with a central memory phenotype1 or polyfunctional T cells.2” Toxicities relate primarily to T cell activation in the presence of abundant cytokines, especially IL-6 (to be blocked by tocilizumab).
The main CAR target in myeloma is B cell maturation antigen (BCMA). Dr Michael Hudecek (University of Würzburg) mentioned a proof-of-concept study in 16 patients with relapsed MM: ORR was 81%, 63% showing a very good PR or CR.3 A murine xenograft model showed that SLAMF7 CAR-T eliminates newly diagnosed and R/R myeloma4 and an international phase I/IIa myeloma study with SLAMF7 CAR-T (CARAMBA) has been started. “This uses a novel virus-free gene transfer (hyperactive Sleeping Beauty transposase) that is cheaper and less toxic.”5
A new CAR target in AML is FMS-like tyrosine kinase (FLT3). FLT3 CAR-T cells show potent anti-leukemia activity in vitro and in vivo and act synergistically with FLT3-inhibitor crenolanib, which enhances FLT3 expression on AML cells with an internal tandem FLT3 duplication.6 According to Hudecek, FLT3 CAR-T should be tested in high-risk patients prior to transplantation for the induction of MRD-negativity.
Finally, CD44v6 CAR-T cells are possibly effective in AML and myeloma and are now tested in an Italian phase I-trial.
What is required to be(come) a CAR-T cell center of excellence? “Firstly experience with advanced cell therapy, preferably allogeneic stem cell transplantation, and FACT-JACIE certification,” explained Prof Stephan Mielke (Karolinska Institutet Stockholm).
“Also we need experts who can treat underlying diseases and it is crucial to collaborate. We need an academic program favoring translation. Furthermore, we need an excellent cooperation with the industrial partners on research and clinic. It is important to have the right mix of academic and industrial trails, avoiding compassionate or off-label use, and standard of care. That requires interdisciplinary platforms on topics as apheresis, ICU, pharmacy, clinical trial office, laboratory, neurology, etc., and also sufficient human and financial resources. We need to reach out to facilitate treatments on a regional and country-based level. But most importantly: we need to put data together on a European level, with outcome-based research and adjustments with respect to PFS, toxicity, QoL, and value-based health care.”
1. Fraietta JA, et al. Nature 2018;558:307-12.
2. Rossi J, et al. Blood 2018, Epub
3. Brudno JN, et al. J Clin Oncol 2018, Epub
4. Gogishvili T, et al. Blood 2017, Epub
5. Mátés L, et al. Nat Genet 2009;41:753-61.
6. Jetani H, et al. Leukemia 2018;32:1168-79.
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