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Science Translational Medicine. New immunotherapy for multiple myeloma proves in the lab to be more effective than CAR-T treatment already in use Researchers at the Spanish National Cancer Research Center (CNIO) and the 12 de Octubre University Hospital have developed a new cell-based immunotherapy to treat multiple myeloma The new immunotherapy is based on STAb cells and has yet to pass clinical trials The study is published in Science Translational Medicine, with head of the H12O-CNIO Cancer Immunotherapy Clinical Research Unit Luis Álvarez-Vallina as senior author BCMA-specific STAb-T cells (red) recognize and attack myeloma cells (blue). Credit: Anaïs Jiménez-Reinoso (Cancer Immunotherapy Clinical Research Unit H12O-CNIO) and Manuel Pérez and Isabel Peset (Confocal Microscopy Unit) / CNIO. Immunotherapy is already improving treatment options for many cancer types, but research groups keep exploring ways to boost the body’s immune response against the tumor. Researchers at the Spanish National Cancer Research Center (CNIO) and the 12 de Octubre University Hospital in Madrid have developed a new immunotherapy to treat multiple myeloma that shows, in the laboratory, to be more effective than the immunotherapy currently used as preferred treatment. The new immunotherapy is based on the so-called STAb cells. It has yet to pass clinical trials and therefore it will be at least two years before it reaches the patients. The study is published in Science Translational Medicine, with the leader of the H12O-CNIO Cancer Immunotherapy Clinical Research Unit Luis Álvarez-Vallina as senior author. It is a collaboration with the Josep Carreras Leukemia Research Institute; the Hospital Clínic of Barcelona; the University of Salamanca and the Complutense University of Madrid. STAb cells Multiple myeloma is the second most common hematological cancer in adults, just after lymphomas. “In recent years these cancers have begun to be treated with CAR-T cell immunotherapy,” explains Luis Álvarez-Vallina, “which has meant a substantial improvement over previous therapeutic tools. In spite of this, and although patients now have longer survival times, a significant proportion of patients experience relapse, and relapse treatments are needed”. Advantages over conventional CAR-T CAR-T cell therapy (Chimeric antigen receptor T-cell therapy, CAR-T for short), involves modifying the diseased person’s T-lymphocyte immune cells (white blood cells) in the laboratory so that they acquire the capacity to recognize and fight tumor cells. The new study on Science Translational Medicine compares this treatment with another cellular immunotherapy based on STAb-T cells. In both cases, the cells modified in the laboratory recognize the same antigen, called BCMA, which is only present in tumor cells. In this way, the modified cells target and attack only cancer cells. The results show that STAb-T cells outperform CAR-T cells in that they recruit natural, non-modified T cells in the body, to also fight cancer cells, thus amplifying the effect of the therapy. In addition, STAb-Ts overcome an element that slows down CAR-Ts. In some patients with multiple myeloma, the BCMA antigen –which identifies tumor cells – is found in soluble form when there is a high tumor burden. The fact that the antigen is soluble hinders the activity of CAR-T cells but does not affect STAb-T cells, the new result shows. Immunological memory “Finally, we also demonstrated that STAb-T cells generate immunological memory,” says Álvarez-Vallina. After recapitulating the disease in animal models and treating them with STAb-T cells, the team obtained cells from various organs –mainly spleen and bone marrow– and observed new memory STAb-T cells being produced. “This is important,” explains Álvarez-Vallina, “because the persistence of CAR-T cells in the body, i.e. immunological memory, is related to the extent of the antitumor effect and, therefore, to a better control of the disease. The fact that we have shown that memory cells are also generated in STAb-T immunotherapy probably indicates that we could have long-term control of the disease in treated patients”. The research group aims to conduct a clinical trial with the 12 de Octubre University Hospital, in Madrid, to treat patients with this new STAb-T immunotherapy. An immunotherapy with STAb-T stab cells is already in trial in patients with B-cell acute lymphoblastic leukemia (B-ALL). Funding Dr. Luis Álvarez-Vallina’s group is funded by the Ministry of Science and Innovation, the Carlos III Institute of Health, the Community of Madrid, the CRIS Foundation to beat Cancer, the Spanish Association Against Cancer and the La Caixa Foundation. The Josep Carreras Leukemia Research Institute group is funded by the Ministry of Science and Innovation, the Carlos III Institute of Health, the European Research Council, and the La Caixa Foundation. Reference article “Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo”, Science Translational Medicine, 2024. DOI: https://doi.org/10.1126/scitranslmed.adg7962 https://www.cnio.es/en/news/new-immunotherapy-for-multiple-myeloma-proves-in-the-lab-to-be-more-effective-than-car-t-treatment-already-in-use/

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo https://www.science.org/doi/10.1126/scitranslmed.adg7962 Editor’s summary Taking a STAb at cellular therapy. Multiple myeloma is a hematological cancer with limited treatment options, particularly after relapse. Chimeric antigen receptor (CAR) T cells are being explored for multiple myeloma, much like for other hematological malignancies, but patients still relapse. Here, Díez-Alonso et al. developed STAb-T cells, which, rather than express a CAR, secrete T cell–engaging antibodies targeting B cell maturation antigen (BCMA) and CD3. The authors compared STAb-T cells with traditional CAR-T cells in vitro and in vivo, showing that the STAb-T cells more effectively killed target cells at low frequencies and were resistant to inhibition mediated by soluble BCMA released from myeloma cells, preventing immune escape. This translated to improved in vivo efficacy in a murine multiple myeloma model, supporting further development of BCMA-specific STAb-T cells as a therapeutic for this and other hematological malignancies. —Courtney Malo Abstract Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

In Spain, Madrid first patient cured of multiple myeloma. https://www.cnio.es/en/news/new-immunotherapy-for-multiple-myeloma-proves-in-the-lab-to-be-more-effective-than-car-t-treatment-already-in-use/

I am 74 years old and was diagnosed with CLL about a year and a half ago. At the moment, I am in the test and watch phase.

Hi Everyone, Many of us are diagnosed with high-risk myeloma. The simple mention of high-risk triggers a mountain of questions and, more often than not, considerable anxiety. The notion of high-risk has a negative connotation and we tend to attach too much significance to it. Consequently we quickly spiral into doom and gloom. I was diagnosed with 1q gain (4 copies) combined with t(4;14). The prognosis for my cytogenetic profile is quite poor. Yet, 16 years after diagnosis, with 5 lines of treatment under my belt, including CAR T-cell therapy (Abecma) 3 years ago, I have responded well and today enjoy amazing quality of life. I dare say that I almost feel cured. Rather than focus negatively on the high-risk aspect of my cytogenetic profile, I just tried to reframe my mental stance to the treatments I received. I tried to look at them positively and, miraculously, enjoyed up to 3 years of response for every line. I interpreted that as a sign that my chances of survival were better than the statistics might suggest. By shifting to a positive perspective I empowered myself to just accept the situation and move forward confidently with hope. I would be keen to know how others in the community rise to the challenge of a high risk cytogenetic profile and whether they allow the poor prognosis to weigh on their minds and undermine their wellbeing and perhaps affect decisions. What has been your response to the high-risk diagnosis? What challenges did you manage to overcome? How did the prognosis affect your outlook? How do you perceive your outcome today? Thank you for your thoughts!

Dr. Wants me to have an ASCT. I have read a lot of negative reviews on this procedure. Can I recover and go back to work in 30 days? I’m deployment on the Border it’s hard to be off of work that long. I have alredy had test to see if my body can handle this procedure. I also had a Double by/pass 2.5 years ago and had two stents out in last year. Had two sternum. Wires removed. Was on Revlemid 25Mg and DEX for 2 years Now just on 15 MG of Revlemid. Does this increase life? Thank you MSG Espitia

There are many alternatives to traditional western treatments that I have read about, none of which seem to provide real solutions. The best one can do is stay as healthy as possible, as happy as possible, and as optimistic as possible. I'm now trying our intravenous Vit C. Has anyone tried this?

Hey y'all! This is my first post on this platform. I'm 41 YO with High Risk CLL with complex karyotype, specifically the dreaded TP53 mutation. Sound effects Dun dunn duuun. My husband,who travels for work, and I have a busy 9 year old who is the best kid -fun, kind, helpful, supportive, and silly. I just started Calquence (acalabrutinib) and have been at full dose about a week and a the half. So far overall I'm feeling much better and labs are looking like they're moving in the right direction. The problem is I wake up with these awful headaches, like I can't see straight. I'm working hard to stay hydrated which often means waking up around 3-5 am to use the bathroom and the headache has already started. Caffeine is recommended and helps once I'm up for the day, but I can't take it for my middle of the night wake ups. The headaches make it really difficult to get moving in the morning to be present for my kiddo, so I'm testing out new morning routines for that. Any suggestions for the headaches that won't keep me from getting back to sleep? Any morning routines that have worked well for anyone else? Thanks!

I just joined this group after seeing an email that said to share what helps you because it might help someone else...so here I am to share what helps me most! I have a very active brain and I found after my diagnosis and even now, 2+ years in, I still spend a lot of time thinking about MM especially when I wake in the morning. My tip is: audio books! This has helped me tremendously! I have always been an avid reader but at the beginning of this journey I found it very hard to focus on a book and tried audio books and got hooked. I never thought I'd be a listener but now I am. It's a great way to take your brain away from ruminating and you can start up your book at any time, anywhere! Give it a try, it's great medicine!