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CAR-T Meeting 2022 | Looking into the future of CAR-T therapy: cardiac fibrosis, infections & autoimmune diseases

Raffaella Greco, MD, PhD, San Raffaele Hospital, Milan, Italy, gives an overview of the session on new chimeric antigen receptor T-cell (CAR-T) indications that took place at this year’s EBMT-EHA CAR T-cell Meeting. To begin with, using animal models, Prof. Epstein provided a proof of principle for the development of CAR-Ts for the treatment of cardiac fibrosis. Subsequently, Prof. Mackensen demonstrated that CD19-targeted CAR-Ts induced rapid clinical remission and efficient B-cell depletion, with no notable adverse effects in refractory systemic lupus erythematosus (SLE). Prof. Protzer then shared a promising new therapeutic approach using bispecific T-cell engagers (BiTEs) to treat chronic hepatitis B infection and chronic hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Finally, Dr Scott gave a presentation on engineering T-cells to modulate adverse immune responses and suppress immunogenic disorders, autoimmunity, and allergy. Altogether, these findings reveal the huge potential of CAR-T therapies in many applications beyond hematological malignancies. This interview took place at the EBMT-EHA 4th European CAR T-cell Meeting which was held virtually in 2022.

Transcript (edited for clarity)

Dear colleagues and friends, I am Raffaella Greco, a hematologist in the bone marrow transplantation unit of the San Raffaele Hospital in Milan in Italy. But I’m currently chairing also the EBMT Autoimmune Diseases Working Party, and this is the reason why today I have been asked to give you some highlights on potential new CAR-T indications from the EBMT-EHA CAR-T meeting, we have seen in the few days before...

Dear colleagues and friends, I am Raffaella Greco, a hematologist in the bone marrow transplantation unit of the San Raffaele Hospital in Milan in Italy. But I’m currently chairing also the EBMT Autoimmune Diseases Working Party, and this is the reason why today I have been asked to give you some highlights on potential new CAR-T indications from the EBMT-EHA CAR-T meeting, we have seen in the few days before. The entire meeting was really exciting, and you have seen all the latest clinical results of CAR-T therapy in its main indications, but also some future indications and new standards of care in this field.

I have had particularly the honor to chair together with Professor Michael Hudecek the great session on new CAR-T indications on February 11th. And undoubtedly CAR-Ts represent a turning point in cancer immunotherapy, and the great potential to modulate cell activation and redirect antigen specificity made this CAR-T approach attractive also in new areas, such as autoimmunity, infection, and also inflammation as we have seen in this fascinating session.

We have seen really four outstanding presentations in this session six. One from Professor Jonathan Epstein from Pennsylvania, United States. He presented CAR T-cell applications in cardiac fibrosis, observed in an early, heavy form of myocardial disease. And he demonstrated the efficacy of redirecting T-cell immunotherapy to specifically target pathological cardiac fibrosis from cardiac fibroblasts in the heart. Adoptive transfer of T-cells that express a chimeric antigen receptor against fibroblast activation protein, results in a significant reduction in cardiac fibrosis and restoration of function after injury in animal models. This provides really a proof of principle for the development of these immunotherapeutic drugs for the treatment of cardiac disease, for example.

Importantly, also Professor Andreas Mackensen, from Erlangen, Germany, presented the first data available on the use of CAR-T therapy to treat patients with systemic lupus. The monotherapy approach induced rapid clinical remission of severe and refractory disease with no notable adverse effects up to now. Autoreactive B-cells, as you know, have been a target for lupus patients for a long time, but the efficacy of existing B-cell depleting drugs has been unsatisfactory up to now. Conversely, CAR-Ts, genetically engineered to recognize CD19 may achieve more complete B-cell depletion in this setting. So clinical remission was accompanied by sustained depletion of circulating B-cells in these patients, and the rapid disappearance of antinuclear DNA antibodies is also important in this setting. Long-term follow-up of these patients is needed to properly check whether these B-cells will return and with them eventually autoimmunity without further treatment after CAR-Ts, but the demonstration of the safety and feasibility of this treatment is really encouraging as we have seen. And CAR-T treatment is really a breakthrough into a new era of immunotherapy, also for rheumatic disorders.

Moreover, we have seen the presentation from Professor Ulrike Protzer, from Munich in Germany, and she has focused on T-cell therapy with T-cells redirected against hepatitis B virus-infected cells by virus-specific receptor. This is a promising therapeutic approach for the treatment, potentially, of chronic hepatitis B and hepatitis B-associated cancer, also. She proposed a safety switch mechanism like caspase-9 or herpes simplex virus thymidine kinase. These do limit cytokine release syndrome and hepatotoxicity that potentially can occur due to the high number of target cells in this setting. Overall, T-cells co-expressing caspase-9 and HBV-specific receptor efficiently recognize and kill HBV replicating cells, containing unwanted hepatotoxicity in this particular application.

Finally, we have seen Professor David Scott from Bethesda, United States, and he mentioned the clinical trials with expanded Tregs, in the setting of autoimmunity in taking over the [inaudible] in transplantation and autoimmunity field. While these cells have been used safely in multiple clinical trials, they are polyclonal and the frequency of specific Tregs is very low. Expanded Tregs express a broad repertoire of specificity and have the potential to be nonspecifically immunosuppressive. To overcome this issue and their rare frequency, his lab is focused on the use of specifically engineered Tregs to suppress adverse immune responses in monogenic disorders, but also autoimmunity and allergy. He will clarify the advantages and disadvantages of the different Treg approaches, including TCR, CAR and BAR, demonstrating how Tregs can be made specific to treat a variety of adverse immune responses. So, the choice of which specific receptor to employ mostly will depend on the targeted disease we will have. So, we are really approaching, overall, the future with all these promising and innovative results, paving the way for future studies to further investigate this innovative use of CAR-T therapy to control our immunity and infection. This is bringing a lot of hope for our patients and also their families I hope.

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