Category Archives: Stem Cell Therapy

Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 25452554 (2017).

Article CAS PubMed Central PubMed Google Scholar

Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 25312544 (2017). Together with Schuster et al. (2017), this seminal study validated the efficacy of anti-CD19 CAR-T cell therapy in patients with R/R lymphoma and showed a similar complete response rate (approximately 60%), despite differences in the CAR design and lymphodepletion regimens, setting a new standard of care for patients with R/R lymphomas.

Article CAS PubMed Central PubMed Google Scholar

Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439448 (2018). This study shows the long-term remission rates achieved by tisa-cel (Kymriah, Novartis), a lentiviral-transduced second-generation CD19 CAR-T cell product containing a 4-1BB co-stimulatory domain. This product became the first FDA-approved gene therapy in 2017, when it received approval for paediatric and young adult patients with B-ALL.

Article CAS PubMed Central PubMed Google Scholar

Abramson, J. S. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396, 839852 (2020).

Article PubMed Google Scholar

Wang, M. et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 382, 13311342 (2020).

Article CAS PubMed Central PubMed Google Scholar

Shah, B. D. et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood 138, 1122 (2021).

Article CAS PubMed Central PubMed Google Scholar

Munshi, N. C. et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384, 705716 (2021).

Article CAS PubMed Google Scholar

Berdeja, J. G. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398, 314324 (2021).

Article CAS PubMed Google Scholar

Jacobson, C. A. et al. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J. Clin. Oncol. 38, 30953106 (2020).

Article CAS PubMed Central PubMed Google Scholar

Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US lymphoma CAR T consortium. J. Clin. Oncol. 38, 31193128 (2020).

Article PubMed Central PubMed Google Scholar

Baird, J. H. et al. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood Adv. 5, 143155 (2021).

Article PubMed Central PubMed Google Scholar

Logue, J. M. et al. Cytopenia following axicabtagene ciloleucel (axi-cel) for refractory large B-cell lymphoma (LBCL). J. Clin. Oncol. 37, e14019 (2019).

Article Google Scholar

Schuster, S. J. et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 22, 14031415 (2021).

Article CAS PubMed Google Scholar

Iacoboni, G. et al. Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Cancer Med. 10, 32143223 (2021).

Article CAS PubMed Central PubMed Google Scholar

Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449459 (2018).

Article CAS PubMed Central PubMed Google Scholar

Wang, M. et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J. Clin. Oncol. 41, 555567 (2023).

Article CAS PubMed Google Scholar

Jacobson, C. A. et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 23, 91103 (2022).

Article CAS PubMed Google Scholar

Chong, E. A., Ruella, M., Schuster, S. J. & Lymphoma Program Investigators at the University of Pennsylvania. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N. Engl. J. Med. 384, 673674 (2021). Together with Schuster et al. (2021), this study shows long-term remissions in patients who received tisa-cel for lymphoma (DLBCL, follicular lymphoma and high-grade BCL). The studies demonstrate a complete response rate of 39% and 55%, respectively, with >60% of these patients remaining in remission at 5 years.

Article PubMed Google Scholar

Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, 3142 (2019).

Article CAS PubMed Google Scholar

Laetsch, T. W. et al. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial. J. Clin. Oncol. 41, 16641669 (2022).

Article PubMed Central PubMed Google Scholar

Pasquini, M. C. et al. Post-marketing use outcomes of an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, axicabtagene ciloleucel (Axi-Cel), for the treatment of large B cell lymphoma (LBCL) in the United States (US). Blood 134, 764764 (2019).

Article Google Scholar

Riedell, P. A. et al. A multicenter analysis of outcomes, toxicities, and patterns of use with commercial axicabtagene ciloleucel and tisagenlecleucel for relapsed/refractory aggressive B-cell lymphomas. Blood 138, 2512 (2021).

Article Google Scholar

Pasquini, M. C. et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 4, 54145424 (2020).

Article CAS PubMed Central PubMed Google Scholar

Neelapu, S. S. et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood 141, 23072315 (2023).

CAS PubMed Google Scholar

Jacobson, C. et al. Long-term (4 year and 5 year) overall survival (OS) by 12- and 24-month event-free survival (EFS): an updated analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma (LBCL). Blood 138, 1764 (2021).

Article Google Scholar

Sehgal, A. et al. Lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): primary analysis from the phase 2 PILOT study. J. Clin. Oncol. 40, 70627062 (2022).

Article Google Scholar

Grupp, S. A. et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia. Blood 132, 895 (2018).

Article Google Scholar

Anderson, L. D. et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, for the treatment of patients with relapsed and refractory multiple myeloma: updated results from KarMMa. J. Clin. Oncol. 39, 8016 (2021).

Article Google Scholar

Davis, J., McGann, M., Shockley, A. & Hashmi, H. Idecabtagene vicleucel versus ciltacabtagene autoleucel: a Sophies choice for patients with relapsed refractory multiple myeloma. Expert Rev. Hematol. 15, 473475 (2022).

Article CAS PubMed Google Scholar

Martin, T. et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J. Clin. Oncol. 41, 12651274 (2022).

Article PubMed Central PubMed Google Scholar

Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563571 (2018). This ground-breaking study used genomic and functional techniques to gain significant insights into the factors that influence the response of CD19 CAR-T cell therapy in patients with CLL. Of note, the study identified IL-6/STAT3 signatures within the T cells of responders, shedding light on crucial biomarkers that can be used by physicians to predict treatment outcomes in patients with CLL.

Article CAS PubMed Central PubMed Google Scholar

Curran, K. J. et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood 134, 23612368 (2019).

Article PubMed Central PubMed Google Scholar

Cappell, K. M. et al. Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J. Clin. Oncol. 38, 38053815 (2020).

Article CAS PubMed Central PubMed Google Scholar

Vercellino, L. et al. Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 4, 56075615 (2020).

Article CAS PubMed Central PubMed Google Scholar

Locke, F. L. et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 48984911 (2020).

Article PubMed Central PubMed Google Scholar

Hay, K. A. et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood 133, 16521663 (2019).

Article CAS PubMed Central PubMed Google Scholar

Chan, J. D. et al. Cellular networks controlling T cell persistence in adoptive cell therapy. Nat. Rev. Immunol. 21, 769784 (2021).

Article CAS PubMed Google Scholar

Xia, A., Zhang, Y., Xu, J., Yin, T. & Lu, X. J. T cell dysfunction in cancer immunity and immunotherapy. Front. Immunol. 10, 1719 (2019).

Article CAS PubMed Central PubMed Google Scholar

Zhao, Y., Shao, Q. & Peng, G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell. Mol. Immunol. 17, 2735 (2020).

Article CAS PubMed Google Scholar

Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917927 (2012).

Article CAS PubMed Google Scholar

Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923937 (2014).

Article CAS PubMed Google Scholar

Chauvin, J. M. et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Invest. 125, 20462058 (2015).

Article PubMed Central PubMed Google Scholar

Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37, 11301144 (2012).

Article CAS PubMed Central PubMed Google Scholar

Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776E2785 (2017).

Article CAS PubMed Central PubMed Google Scholar

Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530534 (2019).

Article CAS PubMed Central PubMed Google Scholar

Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 4556 (2019).

Article CAS PubMed Google Scholar

Chong, E. A. et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129, 10391041 (2017).

Article CAS PubMed Central PubMed Google Scholar

van Bruggen, J. A. C. et al. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. Blood 134, 4458 (2019).

Article PubMed Central PubMed Google Scholar

Rossi, J. et al. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 132, 804814 (2018).

Article CAS PubMed Central PubMed Google Scholar

Klebanoff, C. A. et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318334 (2016).

Article PubMed Google Scholar

Link:
Mechanisms of resistance to chimeric antigen receptor-T cells in ... - Nature.com

What is CAR T-cell therapy?

Car-t cell therapy involves genetically engineering T cells isolated from patients or allogeneic donors to express chimeric antigen receptors (CAR) that specifically recognize and kill tumor cells.

As a "living" drug, CAR-T therapy is very different from traditional drugs. It is a new type of precision targeted therapy for the treatment of tumors. Compared with traditional chemotherapy and hematopoietic stem cell transplantation, it is more precise in killing tumor cells and significantly reduces toxic side effects while improving efficacy.

Cytokines in CAR-T cell therapy

Cytokines are pleiotropic and diverse, and enhancing T-cell activation signaling by transgenic expression of cytokines or engineered cytokine receptors has become one of the important strategies for CAR-T therapy. Cytokines not only enhance the expansion and persistence of CAR-T cells, but also enhance their function in immunosuppressive TME.

Cytokines, including interleukins, tumor necrosis factor, interferons, chemokines, colony-stimulating factors, growth factors, etc., are involved in the activation, proliferation, differentiation and survival of various immune cells. CAR-T cells can regulate immune function, and their combination with cytokines can achieve synergistic effects, which has great potential for application in cancer therapy.

The -chain co-receptor family, which includesIL-2,IL-4,IL-7,IL-9,IL-15andIL-21, plays a key role in T cell differentiation, proliferation and internal environment stabilization. The receptors for these cytokines include a common gamma chain (c) and a separate receptor chain for each. IL-2 and IL-15 share IL-2R. Their downstream signals activate members of the STAT family. These cytokines play a role in the proliferation, survival and persistence of CAR-T cells bothin vitroandin vivo.

TheIL-1superfamily of cytokines includes IL-1, IL-1,IL-33, IL-1Ra,IL-18,IL-37, IL-36Ra, IL-36, IL-36, IL-36, andIL-38, which play important roles in innate and adaptive immunity.

The IL-12 cytokine family includesIL-12,IL-23,IL-27, andIL-35, which have different roles in innate and adaptive immune responses, with IL-12 and IL-23 having pro-inflammatory effects, IL-27 having pro- and anti-inflammatory effects, and IL-35 having anti-inflammatory effects.

Cytokines not only enhance the antitumor activity of CAR-T cells, but also modulate other cells within the TME and induce or enhance endogenous tumor-specific immune responses.

Cytokine-release syndrome in CAR-T therapy

Like other anti-cancer drugs, CAR-T therapy has its side effects, such as cytokine storm, neurotoxicity, lifelong B-cell loss, and the most fatal one is cytokine release syndrome (CRS).

CRS, also known as cytokine storm, is a severe systemic inflammatory response syndrome caused by the activation of immune cells and the release of large amounts of cytokines (e.g., interferon, interleukin IL, chemokines, tumor necrosis factor,etc.).

In order to better understand the functions played by different cytokines in CAR-T therapies, develop more functional applications of cytokines, and evaluate the safety of CAR-T therapies, Creative Proteomics can provideLuminex multiplex assaytechnology to simultaneously detect multiple cytokine levels during the development of therapies, such as TNF-, IFN-, IL-6, IL-10, GM-CSF.

Continue reading here:
Cytokines in CAR-T Cell Therapy - PharmiWeb.com

The study from the Catholic University of Korea School of Medicine discovered a compound that greatly increases the ability of cells to regenerate.

A team of researchers from the Catholic University of Korea School of Medicine recently revealed that they have been developing a method of stem cell therapy which allows for more efficient drug delivery at the cellular level, and it could also play a part in bone regeneration. Published in the November issue of Biomaterials, these groundbreaking findings represent the first successful attempt to use saponin-based nanoparticles in stem cell therapy.

According to Korea Biomedical Review, the team found that nanoparticles displayed the potential to promote osteogenic differentiation (the process by which skeletal stem cells form, develop, repair, and maintain) of human mesenchymal (skeletal) stem cells (hMSCs) adult cells obtained from bone marrow, not fetal cell lines and subsequently enhance bone regeneration.

These nanoparticles, based on naturally occurring compounds called saponins found in cells of legume plants, exhibited the capability of rapid cellular absorption as well as the sustained ability to deliver drugs between cells. This sustained intracellular drug delivery capability is important because it could help direct stem cell differentiation, a pivotal aspect of stem cell therapy that directs the pliant stem cells to turn into the desired cell.

The team was able to create a concoction based on the saponin nanoparticles that successfully directed the human mesenchymal stem cells to differentiate into osteoblasts, or cells responsible for bone formation. The study found that the unique properties of the saponin enabled nanoparticles to be absorbed into the stem cells without any prompting (electrical charge) from the researchers and facilitated the formation of cellular pores.

Researchers found success in testing their data on a defective femur bone of a rat. The experimental treatment was shown to regenerate the bone at a much faster rate than normal and the rat recovered completely. The team notes that the nanoparticles allow drugs to remain within cells longer, allowing the drugs to have longer effects before they are vacated.

Professor Koo Hee-beom, of Catholic University of Koreas Catholic Photomedicine Research Institute, commented on the study:

This study shows the potential of nanoparticle-facilitated drug delivery within stem cells, Professor Koo said. We anticipate its broad application in various stem cell therapy domains in the coming years.

Read more at Korea Biomedical Review.

See the original post:
Korean Catholic team makes strides in bone regeneration - Aleteia

Ultimately, the goal is for this therapy to become simpler, for the principles behind the treatment to be applied to a gene editing method that does not require toxic chemotherapy and a month or more in the hospital. While gene therapy will be undertaken by a minority of the sickle cell population, at least initially, these questions will only become more pressing over time.

As will questions of cost. Looking to recently approved gene therapies for comparison, the treatment could carry a price tag of $1 million or more per person. And if this high-cost treatment and necessary chemotherapy and hospitalization are not covered by Medicaid, then this tremendous scientific advance will only accentuate disparities in a disease where disparities are already too prevalent. Finally, for those who do undergo gene therapy, will the worlds that they re-enter acknowledge the complexity of what it means to be cured? Those who have suffered from sickle cell for years often become accustomed to hefty doses of opiates. Their interactions with the medical system are defined by pain and, for so many, by not being believed. Those experiences will continue to reverberate.

Some of the people who are going for gene therapy have been so tremendously affected by sickle cell that basically their whole lives were about being sick, said Dr. Lewis Hsu, the chief medical officer at the Sickle Cell Disease Association of America and the director of the pediatric sickle cell program at the University of Illinois at Chicago. Youre an adult but youve never applied for a job. Other people dont have friends outside their sickle cell peer group, he continued, extrapolating from the experiences of those who have undergone bone marrow transplants. Some people almost need a society re-entry program. And then there are others who have blossomed, gone off and done wonderful things.

When Mr. Holmes returned to his home in Mobile, Ala., after about 90 days of hospitalization at the N.I.H., he found himself with an energy he had never experienced before, a feeling he describes as the newness of life. Though he expected those in his world to be elated by his newfound health, it was not that simple. His wife, accustomed to her role as the caretaker, was unable to adjust to the shift and they ultimately divorced. The adjustment was hard on Mr. Holmes, too. He realized that he had come to terms with the idea that he would die young, but living with the knowledge of all his missed opportunities was almost harder. No one had prepared him for that.

But he carried on. He connected with others suffering from sickle cell disease in Alabama, to offer education and to encourage them to keep fighting the disease and advocating for themselves, to move cities to find good care if they had to. Though he would not be able to fulfill his long-held goal of serving as a Marine, he could keep a job, and found work in the county jail as a corrections officer. It was traumatizing work at first, but work he is good at and for which he is respected. He writes poetry when he has time. And more recently, Mr. Holmes moved out of Alabama to Austin, Texas.

Continued here:
Opinion | A New Sickle Cell Treatment Will Change Lives but ... - The New York Times

The UK regulatory authorities have approved the first ever trial of a revolutionary gene therapy for young children diagnosed with Hunter syndrome, a devastating rare lysosomal storage disorder.

Five children under one year of age with the condition also known as mucopolysaccharidosis type II (MPS II) will be treated with autologous hematopoietic stem cell (HSC) gene therapy.

The children will continue to receive enzyme replacement therapy during treatment, but once the gene therapy begins to work, the research team say part of the trial aims to remove the need for weekly enzyme replacement therapy over the childs lifetime, while the other aim is to safely target the brain disease suffered by these patients.

The combined phase 1 and 2 clinical trial initiated by University of Manchester researchers, is now open to recruitment. AVROBIO, the previous funders of the program, have returned the license to The University of Manchester.

The study will be carried out at Royal Manchester Childrens Hospital (RMCH) in collaboration with the Manchester Centre for Genomic Medicine at Saint Marys Hospital both part of Manchester University NHS Foundation Trust (MFT), will trial the drug for the treatment for this rare inherited disorder, the drug for the treatment for this rare inherited disorder, which was developed over eight years by Brian Bigger, Professor of Cell and Gene Therapy at The University of Manchester.

Professor Bigger and his team this month published a paper in Molecular Therapy clinical Methods which validates the proof-of-concept outcomes findings in mice, providing further long-term efficacy data.

The trial aims to recruit up to five patients with severe MPS II who are aged between three months and 12 months at time of consent. Inclusion criteria are for children in the above age range with a confirmed diagnosis of severe MPSII who may already be on enzyme replacement therapy but have not yet developmentally declined.

It will be a 24-month, single-arm, open label study which will evaluate the HSC gene therapys safety and tolerability, as well as its pharmacodynamic and clinical efficacy.

Children with severe Hunter syndrome cannot properly break down complex sugar molecules and have widespread symptoms including rapid and progressive learning and memory problems, heart and lung dysfunction, hyperactivity and behavioural problems, bone and joint malformations and hearing impairment.

The UK Medicines and Healthcare Products Regulatory Agency (MHRA), Research Ethics Committee (REC), and Health Research Authority (HRA) have all approved the clinical trial application that was submitted by The University of Manchester in August 2022.

Brian Bigger said: Were very excited by the pre-clinical studies we carried out in mice, which showed the potential to correct disease in the body and normalize brain pathology.

The clinical trial will be led by Professor Rob Wynn, Consultant Paediatric Haematologist at RMCH, together with Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at Saint Marys Hospital, and Professor Bigger at The University of Manchester. The University of Manchester will act as trial sponsor.

Children with Hunter syndrome have a missing gene, meaning they cannot produce an important enzyme called iduronate-2-sulfatase or IDS. The gene therapy works by collecting HSCs from the patient and inserting a working copy of the gene into the HSCs using a lentiviral gene therapy vector. The modified HSCs are then infused back into the patient to engraft in the bone marrow. Following successful engraftment of modified HSCs in the bone marrow, these cells start to produce daughter blood cells which contain the IDS gene and enzyme which are distributed throughout the body, including the brain.

Professor Bigger said: This is a next generation stem cell gene therapy approach, which allows transit of the IDS enzyme into the brain. The newly inserted IDS gene produces an IDS enzyme that contains a proprietary ApoEII-tagged sequence, which can bind to ApoE-dependent receptors on the blood brain barrier, and move enzyme into the brain more efficiently, thus potentially normalising brain pathology.

This should speed up delivery of enzyme to the brain, where it is most needed as we can leverage all the enzyme produced by the blood to do this rather than just relying on the engraftment of monocyte cells from the blood into the brain.

He added: Were very excited by the pre-clinical studies we carried out in mice, which showed the potential to correct disease in the body and normalize brain pathology.

Mice with Hunter syndrome treated with the HSC gene therapy showed dramatic improvement in their condition, including normalisation of working memory problems, and skeletal features such as the cheekbone dimensions and the width of the humerus and femur bones.

The trial is the culmination of a more than 15-year collaborative effort with Professor Wynn and Professor Jones at MFT to develop HSC gene therapies for neurological lysosomal disorders and is now the second potential neurological gene therapy that this collaborative team has brought into the clinical setting.

Bob Stevens, chief executive of the MPS society, said: This ground-breaking trial initiated by The University of Manchester offers the possibility of new treatment options in the future for patients with the severest form of MPSII Hunters. We look forward to hearing the outcome of this trial, with cautious optimism and hope that science will offer the chance of a Rare Life Lived Better.

View original post here:
Groundbreaking gene therapy trial for Hunter syndrome opens - Manchester University NHS Foundation Trust

CB-012 is a genome-edited CAR T cell therapy that is produced using the next-generation genome-editing technology platform CRISPR Cas12a chRDNA, which is capable of generating notable genomic integrity and significant specificity.

The FDA has cleared an investigational new drug application for allogeneic antiCLL-1 chimeric antigen receptor (CAR) T Cell therapy CB-012 as a treatment for patients with relapsed/refractory acute myeloid leukemia (AML), according to a press release from Caribou Biosciences.1

Investigators report that CB-012 will be assessed as part of the phase 1 AMpLify study (NCT04853017) in the aforementioned patient population. Experts indicate that CLL-1 has potential as a therapeutic target in the AML space, as it is highly expressed in cancer cells and leukemic stem cells, although it is not seen on hematopoietic stem cells.

There is an urgent need to develop new treatments for patients with relapsed or refractory AML, for which the treatment options are predominantly limited to salvage chemotherapy regimens, Naval Daver, MD, associate professor and director of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in the press release. An allogeneic CAR T cell therapy that could safely and effectively target AML blasts while preserving healthy hematopoietic stem cells could provide a much-needed off-the-shelf option for these patients.

CB-012 is a genome-edited CAR T cell therapy that is produced using the next-generation genome-editing technology platform CRISPR Cas12a chRDNA, which is capable of generating notable genomic integrity and significant specificity. The agent is capable of checkpoint disruption and immune cloaking. CB-012 was designed to target CLL-1positive AML while decreasing the risk of graft-vs-host disease and immune rejection of T cells and natural killer cells.2

CB-012 was engineered with 5 genome edits, and is the first allogeneic CAR T cell therapy, to our knowledge, with both checkpoint disruption through a PD-1 knockout, and immune cloaking through a B2M knockout and B2MHLA-E fusion transgene insertion, Steve Kanner, PhD, Caribous chief scientific officer, explained. Both armoring strategies are designed to improve the antitumor activity of CB-012 that we believe are crucial for targeting this difficult-to-treat indication.

The open-label, multicenter phase 1 AMpLify study will evaluate CB-012 using a 3+3 design in the trials dose escalation portion. Investigators will assess the agent at several ascending doses to decide upon a maximum tolerated dose and/or recommended dose for the dose expansion portion of the study. Notably, the primary outcome of the dose expansion portion of the study is the overall response rate following 1 dose of CB-012.

The trial will include individuals who have not responded to or relapsed following standard treatment. Those who have proliferative disease or have undergone treatment with over 3 previous lines of therapy are ineligible for enrollment. Investigators intend to begin patient enrollment by mid-2024, wherein patients will receive a single infusion of CB-012 at 25x106 CAR T cells or dose level 1.

We look forward to initiating patient enrollment in the AMpLify Phase 1 trial by the middle of 2024 to evaluate the safety and tolerability of CB-012 in patients suffering from AML, Rachel Haurwitz, PhD, president and chief executive officer at Caribou Biosciences, concluded.

View original post here:
FDA Clears IND Application for AntiCLL-1 CAR T-Cell Therapy for ... - Cancer Network