The FDA approval was based on results from the DESTINY-Breast04 study, which found that Enhertu improved both progression-free survival and overall survival in people diagnosed with previously treated metastatic HER2-low breast cancer when compared with doctors’ choice of chemotherapy.

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The ideal strategy for treating cancer with cell therapy can vary greatly depending on the type of tumour. Three presentations at this year's annual meeting of the American Association for Cancer Research highlighted how distinct approaches can be used to improve the efficacy of cell therapies for blood cancers or solid tumours. First, younger patients with diffuse midline glioma experienced prolonged benefit after receiving an experimental GD2-directed CAR T therapy developed at Stanford University. Secondly, initial data from a phase 1/2 dose escalation trial showed encouraging clinical activity for patients with testicular cancer and ovarian cancer who received the experimental regimen. Agents used in the trial included BNT211 (BioNTech), an autologous CAR T cell therapy that targets the oncofetal antigen Claudin-6 (CLDN6) and CARVac, an mRNA-based vaccine encoding CLDN6 designed to enhance CAR T cell activity. Finally, another emerging cell therapy uses a completely different effector cell platform. Researchers have combined natural killer cells with a bispecific antibody for patients with relapsed or refractory CD30-positive lymphoma. All patients who received the recommended phase 2 dose of the experimental treatment achieved an objective response to treatment. 

Maraleucel lisocabtagen is a second-line treatment for adults with relapsed or refractory diffuse large B-cell lymphoma. It is a chimeric T-cell therapy directed at the CD19 antigen receptor, commonly known as liso-cel. This therapy induced an initial complete remission in more than half of patients with relapsed or refractory large B-cell lymphoma ineligible for transplantation, results of a phase 2 PILOT trial showed. The multicenter study included 61 patients (median age 74 years; range 53-84; 61% male) with relapsed or refractory B-cell lymphoma. All study participants experienced disease progression after first-line therapy and were ineligible for high-dose chemotherapy and HSCT. Patients received lymphodepleting chemotherapy followed by a single infusion of liso-cel at a target dose of 100 × 10 6 CAR T cells. In addition, a primary analysis of the study revealed a low incidence of treatment-related high-grade cytokine release syndrome and neurotoxicity after a single dose of cell therapy.

An experimental gene-modified CRISPR/Cas9 cell therapy has demonstrated significant and sustained efficacy in patients with transfusion-dependent beta-thalassemia and sickle cell disease. The new data, presented at the European Association of Haematology Hybrid Congress 2022, showed an increase in fetal haemoglobin levels after a single dose of exa-cel, formerly known as CTX001. Exa-cel uses CRISPR-Cas9-mediated ex vivo editing of BCL11A to produce high levels of fetal haemoglobin in red blood cells. In patients, this treatment resulted in the elimination of transfusions in almost all of the 44 patients with beta-thalassemia and the elimination of vaso-occlusive crises in the 31 patients with sickle cell disease. The researchers also observed clinically significant increases in fetal haemoglobin and haemoglobin levels in both groups of patients, with an average proportion of fetal haemoglobin of more than 20% at month 3, rising to about 40% at month 4 and stabilising thereafter. Mean total haemoglobin levels exceeded 11 g/dL after month 3.  

Jonathan Weissman, a member of the Whitehead Institute, and his colleagues have produced the first comprehensive functional map of genes expressed in human cells. The data from this project, published online on 9 June in Cell, associates each gene with its work in the cell. For this project, the researchers used the Perturb-seq method, which uses CRISPR/Cas9 genome editing to introduce genetic modifications into cells, and then uses single-cell RNA sequencing to capture information about the expressed RNAs resulting from a given genetic modification. Since RNAs control all aspects of cell behavior, this method can help decipher the many cellular effects of genetic modifications.  Using human blood cancer cell lines as well as non-cancerous retina-derived cells, the researchers performed a Perturb-seq on over 2.5 million cells and used the data to create a comprehensive map linking genotypes to phenotypes. Once completed, the researchers decided to use their new dataset and examine some biological questions. In the future, the researchers hope to use Perturb-seq on different cell types in addition to the cancer cell line they started with. They also hope to continue exploring their map of gene functions and hope that others will do the same. 

Caribou Biosciences recently announced positive initial clinical trial data for its genetically engineered CAR-T cell therapy candidate CB-010. Caribou is developing CB-010 as a ready-to-use allogeneic anti-CD19 CAR-T cell therapy for relapsed/refractory B-cell non-Hodgkin's lymphoma (r/r NHL-B). The CD19-specific CAR is inserted into the TRAC gene, which encodes the T cell receptor alpha constant. The PD-1 gene is also deleted in these cells. This gene encodes the PD-1 protein that functions as a safety switch on T cells that cancer cells activate to protect themselves from T-cell mediated immune responses. CB-010 is the first allogeneic CAR-T cell therapy with a CRISPR-mediated PD-1 deletion to be approved for clinical trial. CB-001 is being evaluated in the Phase 1 ANTLER trial, and data published to date have shown a 100% overall response rate (ORR, 5 out of 5 patients) and an 80% complete response rate (CR, 4 out of 5 patients) after a single dose at baseline in patients with aggressive r/r NHL. These data make CB-010 the first allogeneic CAR-T cell therapy to achieve a 100% ORR. 

Researchers have initiated a Phase 1 trial (NCT04155749) exploring ACLX-001, a novel CAR T-cell therapy using the ARC-SparX platform, in patients with relapsed multiple myeloma. ARC-SparX is a universal cell therapy platform composed of soluble antigen-receptor X-linker (SparX) proteins designed to target BCMA to myeloma cells. This is combined with a separate dose of antigen receptor complex-T (ARC-T) cells, which are designed to activate only when engaged with a SparX protein that has bound to a myeloma cell. The combination of ARC-T cells and SparX protein forms ACLX-001. The ARC-T cells and SparX proteins use Arcellx's new synthetic binding scaffold called D-Domain. According to drugmaker Arcellx, the first patient received the study treatment in May 2022. In the clinical trial, patients may receive ARC-T cells, SparX-001 or both, and treatment may be escalated based on correlative clinical data, including SparX-00 pharmacokinetics and ARC-T expansion.The trial's primary endpoints are the incidence of treatment-related adverse events, including dose-limiting toxicities over 24 months, and the establishment of the recommended phase 2 dose. The trial is still recruiting patients. First data from the Phase 1 study are expected in 2023.   

In the field of CAR T-cell therapies, there are three major unmet needs. The biggest thing that needs to be improved is access to treatment because at the moment all these drugs are only approved in the very late relapsed/refractory stage. Often there are patients waiting for these drugs who cannot get to that stage. This is one of the biggest unmet needs. Another unmet need in myeloma is product-specific treatments. With cilta-cel, for example, we are seeing extremely high response rates and durable remissions. The hope is that we will continue to see no neurotoxicity, the opposite of what was seen in CARTITUDE-1. The good news is that we have not seen neurotoxicity so far with the mitigation strategies the researchers are using, but they need to follow patients long-term to confirm this. The unmet need with ide-cel is that response rates are about 40% and PFS is about 20 months in the highly refractory patient population. Researchers need to do a better job of increasing response rates and also improving the duration of response.  

Many new drug delivery models and systems have emerged in recent years, allowing scientists to consider the application of ribonucleic acid (RNA) based drugs in the treatment, prevention and diagnosis of a range of disorders. Hydrophilic anionic RNA therapeutic molecules are unable to cross the cell membrane without delivery systems or chemical modification. Biodegradable, biocompatible and low toxicity nanomaterials are now being used as RNA nanocarriers. These include polyethyleneimine (PEI) lipids, poly(lactic-coglycolic acid), magnetic nanoparticles, carbon nanotubes, gold nanoparticles and silica nanoparticles. Lipid nanoparticles (LNPs) are currently used in vaccines and nucleic acid drugs due to their easy manufacture and compliance with the above criteria. Origami-like RNA nanostructures are also promising vehicles, as are virus-like particles (VLPs). As RNA carriers develop, the use of new vehicles, including nanodots and carbon nanotubes, and functionalized systems is increasing

Tisagenlecleucel and axicabtagen ciloleucel are autologous chimeric T cell antigen receptor therapies directed against CD19. Tisagenlecleucel may be less toxic than the axicabtagen ciloleucel for patients with relapsed or refractory follicular lymphoma, according to the study results. Patients who received the axicabtagen ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) for advanced follicular lymphoma had a significantly higher incidence of cytokine release syndrome and neurotoxicity than those who received tisagenlecleucel (Kymriah, Novartis). Dickinson and colleagues conducted a matched indirect comparison study based on propensity score weighting to compare populations from different trials while adjusting for different characteristics of each patient population. The results showed similar efficacy results between the pre- and post-weighting studies, while tisagenlecleucel showed significantly lower rates of overall and high-grade CRS or neurotoxicity.  

The FDA has granted orphan drug designation to ALLO-605, a CAR T-cell therapy for adults with relapsed or refractory multiple myeloma that targets the B-cell maturation antigen on the surface of cancer cells. The ready-to-use CAR T-cell therapy is derived from healthy donor-induced pluripotent stem cells and has been developed using Allogene's proprietary TurboCAR platform to enhance their potency and function. ALLO-605 is currently being evaluated in the IGNITE Phase 1 trial. The dose escalation study is designed to evaluate the safety, feasibility and recommended Phase 2 dose of ALLO-605 for patients with relapsed or refractory multiple myeloma or other BCMA-positive malignancies. The trial uses CAR T-cell therapy in combination with ALLO-647, a monoclonal antibody to CD52, in the study's lymphodepletion regimen prior to ALLO-605 infusion.   

The CAR T-cell therapies axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (Kymriah) and lisocabtagene maraleucel (liso-cel; Breyanzi) are all FDA-approved for the treatment of patients with DLBCL. However, patients with primary and secondary CNS lymphoma have been excluded from clinical trials using these agents due to the risk of toxicities such as CRS and ICANS. According to a systematic review and analysis of published data presented at the 2022 Transplantation and Cell Therapy Meetings, Axicabtagene ciloleucel, Tisagenlecleucel and liso-cel elicited responses without increased risk of cytokine release syndrome or effector immune cell-associated neurotoxicity in patients with primary or secondary central nervous system (CNS) large B-cell lymphoma (LBCL). In the study, 47.6% of the patients evaluated were male. In addition, 28.3% of patients had primary CNS lymphoma and 71.8% of patients had secondary CNS lymphoma. Of these patients, 53.5% achieved CR, 14.1% had PR and 36.6% had progressive disease. The PFS rates at 1 month, 3 months, 6 months and 12 months were 72.1%, 57%, 44.2% and 37.5%, respectively. 

The FDA has granted accelerated designation to PRGN-3006 for the treatment of adults with relapsed or refractory acute myeloid leukemia. PRGN-3006 (Precigen Inc.) is a CAR T cell therapy that targets the CD33 protein on the surface of cancer cells. This investigational therapy, designed to reduce manufacturing time to 1 day, is based on Precigen's UltraCAR-T therapeutic platform. The therapy uses the Sleeping Beauty non-viral gene editing system to simultaneously express CD33-targeted CAR, membrane-bound interleukin-15 and a therapeutic "kill switch" that conditionally eliminates CAR T cells for increased safety. PRGN-3006 is being evaluated in a single-center Phase 1/phase 1B dose escalation/extension study to determine safety and recommended Phase 2 dose for adults with relapsed or refractory AML, high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia. Study participants will receive a single IV dose of the treatment with or without prior lymphodepletion. Interim results from the study, presented last year at the ASH Annual Meeting, showed an overall response rate of 50% in the first six patients in the lymphodepletion cohort. Safety results showed no dose-limiting toxicities. One of the 15 patients developed a grade 3 cytokine release syndrome. 

MaxCyte, Inc, a commercial cell engineering company specializing in the provision of platform technologies has a portfolio of instruments that are the next generation of advanced, clinically validated electroporation technology for complex and scalable cell engineering. Offering high transfection efficiency, seamless scalability and enhanced functionality, their ExPERT™ platform notably delivers the high-end performance essential to enable the next wave of biological and cell-based therapies. The company announced the signing of a strategic platform licence (SPL) with LG Chem Ltd. This company obtains non-exclusive clinical and commercial rights to use MaxCyte's flow electroporation technology and ExPERT™ platform. In return, MaxCyte is entitled to receive platform licensing rights and revenues related to the programme. LG Chem is thereby strengthening its anti-cancer business through the advanced construction of cellular drug platform technologies. LR19023, its next-generation CAR-T cell therapy, is currently in preclinical stage and under development as a solid anti-cancer therapeutic.

GC012F (Gracell Biotechnologies) is an autologous, genetically engineered, bispecific CAR-T that targets B cell maturation antigen (BCMA) and CD19 proteins on the surface of cancer cells. BCMA is universally expressed on malignant plasma cells and is a well-established target for multiple myeloma, while CD19 is expressed on both myeloma cells and their progenitor cells. The new cell therapy, which previously received FDA orphan drug designation, is manufactured within 24 hours of apheresis using Gracell's proprietary FasT CAR platform. The investigators chose to use a dual-targeted CAR-T manufactured in one day or less for this study population of heavily pre-treated multiple myeloma patients to reduce the risk of disease progression prior to CAR-T infusion. Twenty-five (89.3%) of 28 patients achieved objective treatment responses after a single infusion of GC0-12F, including 21 (75%) with a negative complete response to minimal residual disease (MRD) or a strict complete response to treatment. Twenty-four (86%) patients had a very good partial response or better.

Beta thalassaemia and sickle cell disease are caused by genetic mutations that affect the adult form of haemoglobin. However, some people have few or no symptoms despite having one of the mutations that normally cause these disorders, because their bodies continue to produce foetal haemoglobin into adulthood. A CRISPR-based treatment, called exa-cel, has therefore been developed that aims to mimic this by extracting blood-producing stem cells from people's bone marrow, using CRISPR gene editing to deactivate the gene that disables fetal haemoglobin production, and then reintroducing the edited cells into each person. Initial promising results for the first people to be treated have recently been published. Results from phase II trials testing the effectiveness of the approach in 75 people have also been announced. In addition, clinical trials are being expanded to include children under 12 years of age after the therapies proved effective in ongoing trials involving people aged 12 to 35. The aim is to treat children early enough to prevent them from developing lasting damage from these inherited disorders. 

GC012F is an autologous, genetically engineered, bispecific CAR-T that targets B-cell maturation antigen and CD19 proteins on the surface of cancer cells. The new cell therapy, which has previously received FDA orphan drug designation, is manufactured within 24 hours of apheresis using Gracell's proprietary FasT CAR platform. A single dose of an investigational chimeric antigen receptor T-cell therapy induced an objective response in up to 90% of patients with relapsed or refractory multiple myeloma, results from the Phase 1 study showed. Data from the trial, presented at the ASCO Annual Meeting, indicated that the agent had a manageable safety profile. Twenty-five (89.3%) of the 28 patients achieved objective treatment responses after a single infusion of GC0-12F, including 21 (75%) with a negative complete response to minimal residual disease or a strict complete response to treatment. Twenty-four (86%) patients had a very good partial response or better. Researchers reported few cases of high-grade cytokine release syndrome and no treatment-related neurotoxicity.