At a glance
Allogeneic chimeric antigen receptor (CAR) T-cell therapy TruUCAR™ GC027 developed by Gracell Biotechnologies, induced early complete remission (CR) and demonstrated a manageable safety profile in its first-in-human trial for patients with adult relapsed/refractory (R/R) T-cell acute lymphoblastic leukaemia (T-ALL) 
CAR T-cell therapy is potentially life-saving and should therefore continue amidst the SARS-CoV-2 (COVID-19) pandemic where clinicians should select patients appropriately, evaluate resource availability and take the necessary precautionary measures against infection
TruUCAR™ GC027 phase 1 study data
The preliminary efficacy data of allogeneic CAR T-cell therapy TruUCAR™ GC027 in its first-in-human trial for R/R T-ALL was announced by its developer, Gracell Biotechnologies, at the American Association for Cancer Research (AACR) Virtual Meeting 2020 held on April 28 . The five R/R T-ALL patients were aged 19-38 years with a median of five prior lines of therapy. After a 6-day course of preconditioning chemotherapy, each received a single infusion of GC027 in one of three dose levels; 6 x 106 cells/kg (dose level 1), 1.5 x 107 cells/kg (dose level 2) and 1 x 107 cells/kg (dose level 3).1 No patient received prior or post-infusion haematopoietic stem cell transplantation (HSCT) . CAR T-cell expansion measured by qPCR started as early as day 1 post-infusion with no direct correlation between tumour burden and peak cell expansion observed . At the day 28 follow-up, all five patients had achieved complete remission (CR) with or without complete blood count recovery (CR/CRi) . Four patients achieved minimum residual disease (MRD) negative CR, three of which remained MRD negative at further follow-up evaluations up to day 161. One patient who had MRD positive CR at day 14, relapsed at day 29 . All patients had experienced grade 3 or above cytokine release syndrome (CRS), a frequent severe adverse event associated with CAR T-cell therapy, however, symptoms were manageable and resolved after treatment and supportive care . One patient also experienced prolonged cytopenia due to fungal infection and was treated with anti-fungal therapy. No neurotoxicity or graft-versus-host disease (GvHD) was reported .
Allogeneic CAR T-cell therapy for T-cell malignancies
The development of CAR T-cell therapies for T-ALL has been relatively delayed compared with those for B-cell ALL (B-ALL), largely due to unintended CAR T-cell fratricide and contamination of CAR T-cell products with malignant T-cells . Furthermore, there is a risk of GvHD with allogeneic T-cells. To date, there are only two approved CAR T-cell therapies approved by the US Food and Drug Administration (FDA): Kymriah for the treatment of R/R B-ALL and diffuse large B-cell lymphoma (DLBCL), and Yescarta which is also indicated for DLBCL [3–5]. GC027 is a second generation CAR that uses T-cells from healthy donors and CRISPR/Cas9 technology to genetically disrupt T-cell receptor-alpha and CD7 to overcome GvHD and fratricide, respectively . Allogeneic therapies also offer other potential advantages over autologous approaches such as the immediate availability of cryopreserved batches and possible standardisation of the CAR T-cell product . T-ALL is a rare but aggressive form of ALL with high relapse rates following chemotherapy and next-line treatments . Therefore, CAR T-cell therapies such as GC027 could provide critical alternative options for those with R/R disease. Although preliminary, results of the ongoing phase 1 study described above are encouraging and among the first human data demonstrating efficacy of allogeneic CAR T-cell therapy for T-cell malignancies.
Impact of COVID-19 on CAR T-cell treatment
Elsewhere in the world, such as in the US, most CAR T-cell therapy studies have been halted due to the COVID-19 pandemic. Many healthcare organisations and societies have provided recommendations for healthcare professionals on the management of patients in the setting of COVID-19, with the aim of reducing the risk of infection, particularly in high-risk patient groups and preserving intensive care unit (ICU) bed availability at their respective centres. The CAR T-cell Consortium, formed of investigators from 8 US academic institutions, recently published consensus recommendations on the use and management of CAR T-cell therapy during the pandemic . As CAR T-cell therapy is potentially life-saving in patients with R/R ALL and DLBCL, authors state that centres should continue to offer this treatment using appropriate selection criteria and strict infection control precautions . CAR T-cell therapy should be preferentially given to those who are most likely to benefit based on prognostic factors, who have no effective alternative treatment options, and in whom the risk of CAR T-cell toxicities is lower to minimise resource utilisation . This includes continuation of phase 2 studies which may offer substantial long-term benefit and a possible cure. Phase 1 studies designed to demonstrate safety and phase 3 studies comparing CAR T-cell therapy with standard of care options are advised to be temporarily discontinued . Availability of tocilizumab should be considered for the management of CRS after CAR T-cell therapy, particularly as there is growing evidence to suggest that tocilizumab reduces the duration and severity of COVID-19 symptoms, which may result in shortages . Centres should reserve at least 2 doses of tocilizumab per patient before CAR T-cell infusion as well as early use at the onset of grade 2 CRS. Studies of CRS prevention and treatment should also continue during the pandemic as data could significantly improve safety and contribute to preserving scarce resources . COVID-19 testing at various time points during the CAR T-cell treatment process with a guideline of 48-72 hours prior to leukapheresis, lymphodepletion and 7 days of CAR T-cell infusion . If patients are COVID-19 positive, they are recommended to delay treatment for a minimum of 14 days from symptom resolution in accordance with current Centres for Disease Control and Prevention (CDC) and American Society for Transplantation and Cellular Therapy (ASTCT) guidelines . Clinicians are advised to balance the risk of delaying treatment against the risk of disease progression on an individual basis . Authors concluded that proceeding with CAR T-cell therapy during the pandemic will require several risk-benefit discussions, however, patients who are in need and likely to benefit should not defer treatment as it is unclear when the COVID-19 situation will ease . Although CAR T-cell therapy is a relatively complex procedure requiring intensive resources during a difficult time, healthcare professionals continue to ensure that this potentially curative option is available to treat R/R ALL and DLBCL, which remain significant unmet medical needs.
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