{"product_id":"a-new-car-t-cell-therapy-for-children-with-hard-to-treat-neuroblastoma-results-of-a-27-patient-trial","title":"A New CAR T-Cell Therapy for Children With Hard-to-Treat Neuroblastoma: Results of a 27-Patient Trial","description":"\u003cp\u003eIn a phase 1–2 clinical trial, 27 children with relapsed or refractory high-risk neuroblastoma received GD2-CART01, a third-generation CAR T-cell therapy that targets the GD2 protein on tumor cells and includes a built-in safety switch. The treatment was feasible and safe: no dose-limiting toxic effects occurred. Cytokine release syndrome developed in 20 of 27 patients (74%) and was mild in 19 of those 20 (95%). The recommended dose was 10×10⁶ CAR-positive T cells per kilogram of body weight. Seventeen of 27 patients (63%) responded to treatment, including 9 complete responses and 8 partial responses, and among patients who received the recommended dose, 3-year overall survival was 60% and event-free survival was 36%.\u003c\/p\u003e\n\n\u003ch1\u003eA New CAR T-Cell Therapy for Children With Hard-to-Treat Neuroblastoma: Results of a 27-Patient Trial\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#what-is\"\u003eWhat Is GD2-CART01?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#patients\"\u003eWho Took Part in the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#manufacturing\"\u003eMaking the Treatment for Each Patient\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eSafety Results: Side Effects and Toxic Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#suicide\"\u003eThe Safety Switch: How the Suicide Gene Worked\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#expansion\"\u003eHow the CAR T Cells Grew and Survived in the Body\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#response\"\u003eTreatment Responses: How Well It Worked\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#survival\"\u003eSurvival Results\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#special\"\u003eThree Patients With an Unusual and Encouraging Course\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eWhat These Findings Mean for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eWhat Patients and Families Should Know\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a 27-patient trial, GD2-CART01 was feasible and safe for children with relapsed or refractory high-risk neuroblastoma, with no dose-limiting toxic effects.\u003c\/li\u003e\n\u003cli\u003eCytokine release syndrome occurred in 74% of patients but was mild in 95% of those cases; no central neurotoxic effects developed.\u003c\/li\u003e\n\u003cli\u003eSeventeen of 27 patients (63%) responded, including 9 complete and 8 partial responses; at the recommended dose, 3-year overall survival was 60%.\u003c\/li\u003e\n\u003cli\u003eThe built-in safety switch worked in one patient, rapidly eliminating transferred cells; the cells later re-expanded and the patient remained in complete response.\u003c\/li\u003e\n\u003cli\u003eThis was a small, single-center trial without a comparison group, so GD2-CART01 remains investigational and is not yet a standard treatment option.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\u003cp\u003eChimeric antigen receptor (CAR) T-cell therapy is a valuable treatment for relapsed or refractory B-cell cancers. In solid tumors, however, the path to an effective CAR T-cell therapy has been more difficult.\u003c\/p\u003e\n\n\u003cp\u003eNeuroblastoma is the most common extracranial solid tumor in children. It is responsible for 11% of all deaths from cancer in the pediatric population. Almost half of patients have high-risk disease at diagnosis, and the 5-year event-free survival among these patients is 40 to 50%.\u003c\/p\u003e\n\n\u003cp\u003eChildren in whom first-line therapy fails have a very low probability of recovery with subsequent treatments. Their prognosis is dismal, with long-term survival of approximately 5 to 10%.\u003c\/p\u003e\n\n\u003cp\u003eNeuroblastoma cells express high levels of a molecule called disialoganglioside GD2. Targeting GD2 with monoclonal antibodies has been associated with a significant increase in survival among high-risk patients. These findings indicate that neuroblastoma is sensitive to immunotherapy and that GD2 is a relevant target.\u003c\/p\u003e\n\n\u003cp\u003eFew early-phase clinical trials of GD2-targeted CAR T cells had shown that the approach was feasible, and few objective responses had been reported. The researchers developed a GD2-directed CAR construct that incorporates two costimulatory domains: CD28 and 4-1BB.\u003c\/p\u003e\n\n\u003cp\u003eTo address potential neurotoxic effects (harm to the nervous system) associated with third-generation CAR T cells, the researchers also included the gene for inducible caspase 9 (iC9) as a safety switch. This switch allows the transferred cells to be killed if they cause dangerous toxic effects. This article reports the 3-year results of the phase 1–2 clinical trial.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is\"\u003eWhat Is GD2-CART01?\u003c\/h2\u003e\n\u003cp\u003eGD2-CART01 is an autologous CAR T-cell therapy. \"Autologous\" means the cells come from the patient's own body. \"Third-generation\" means the CAR construct includes two costimulatory domains, CD28 and 4-1BB, which help the T cells activate and persist.\u003c\/p\u003e\n\n\u003cp\u003eThe treatment works by reprogramming a patient's own T cells to recognize and attack cells that carry the GD2 molecule. Neuroblastoma cells carry high levels of GD2, which makes them a target for this therapy.\u003c\/p\u003e\n\n\u003cp\u003eThe therapy also contains an inducible caspase 9 (iC9) suicide gene. This gene acts as a safety switch. If the transferred cells cause dangerous side effects, doctors can activate the switch to eliminate them.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\u003cp\u003eThe trial was an academic, phase 1–2 clinical trial conducted at the IRCCS Ospedale Pediatrico Bambino Gesù in Rome. The trial assessed the feasibility and safety of GD2-CART01 in patients with relapsed or refractory high-risk neuroblastoma. It also tested the treatment efficacy of the recommended dose.\u003c\/p\u003e\n\n\u003cp\u003eThe phase 1 portion was a dose-finding trial. It followed an escalation and de-escalation schema. The first patients received GD2-CART01 at a dose of 3×10⁶ CAR-positive T cells per kilogram of body weight. Two dose-escalation levels were specified: 6 and 10×10⁶ CAR-positive T cells per kilogram.\u003c\/p\u003e\n\n\u003cp\u003eIf the initial dose level was associated with dose-limiting toxic effects, two additional de-escalation dose levels were planned: 2 and 1×10⁶ CAR-positive T cells per kilogram. Both the national competent authority of Italy and the institutional review board of IRCCS Ospedale Pediatrico Bambino Gesù approved the trial.\u003c\/p\u003e\n\n\u003cp\u003ePatients between the ages of 1 and 25 years with a diagnosis of high-risk neuroblastoma were enrolled in the phase 1 trial if they had relapsed disease. Patients were also enrolled if they had persistent or progressive disease during first-line treatment.\u003c\/p\u003e\n\n\u003cp\u003eIn the phase 2 trial, patients with metastatic disease and MYCN amplification could be enrolled after completion of first-line treatment, even if they had a complete response. MYCN is a gene; MYCN amplification means the gene is present in extra copies.\u003c\/p\u003e\n\n\u003cp\u003eBefore infusion of GD2-CART01, all patients received the same lymphodepleting chemotherapy. This chemotherapy uses fludarabine and cyclophosphamide. Lymphodepletion means reducing the number of lymphocytes (a type of immune cell) to make room for the new CAR T cells.\u003c\/p\u003e\n\n\u003cp\u003eDisease response was evaluated with the Revised International Neuroblastoma Response Criteria, using European International Society of Paediatric Oncology Neuroblastoma Group (SIOPEN) scoring. The first disease assessment was performed in every patient at week 6 after GD2-CART01 infusion.\u003c\/p\u003e\n\n\u003cp\u003eRadiologic and magnetic resonance images and SIOPEN scores were evaluated in a blinded fashion. A dedicated radiologist and a nuclear radiologist performed this review. High disease burden was defined as at least one of the following:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eBulky disease, defined as a mass that was at least 5 cm in the greatest dimension\u003c\/li\u003e\n\u003cli\u003eBone marrow infiltration of greater than 50%\u003c\/li\u003e\n\u003cli\u003eAn MIBG (metaiodobenzylguanidine) SIOPEN score higher than 7, on a scale of 0 to 72, with higher scores indicating greater dissemination of disease\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eFor the statistical analysis, patient characteristics and trial outcomes were described with usual summary statistics. These included counts and percentages for categorical factors, and the mean, median, or range for continuous factors. The median follow-up was derived with Schemper's method.\u003c\/p\u003e\n\n\u003cp\u003eCox models with one or two covariates were used to derive hazard ratios with 95% confidence intervals for overall and event-free survival. The assumption of proportional hazards was assessed with the use of supremum tests.\u003c\/p\u003e\n\n\u003ch2 id=\"patients\"\u003eWho Took Part in the Study\u003c\/h2\u003e\n\u003cp\u003eA total of 30 patients underwent screening, and 27 were enrolled and received treatment between January 2018 and October 2021. Three patients were excluded: 2 because of rapidly progressing disease and 1 because of a psychiatric disorder.\u003c\/p\u003e\n\n\u003cp\u003eOf the 27 patients, 18 (67%) were male and 9 (33%) were female. The median age was 6.7 years, with a range of 2.7 to 18.6 years. The median number of previous treatments was 3, with a range of 1 to 6.\u003c\/p\u003e\n\n\u003cp\u003eAt enrollment, 12 patients (44%) had refractory disease, 14 patients (52%) had relapsed disease, and 1 patient (4%) had no evidence of disease after NB-HR01 first-line treatment. NB-HR01 first-line treatment consisted of therapy according to the SIOPEN Trial for High-Risk Neuroblastoma protocol. That therapy included an induction phase with intensive chemotherapy, surgery, high-dose chemotherapy with reinfusion of autologous stem cells, radiotherapy, differentiating treatment with isotretinoin, and immunotherapy with the anti-GD2 monoclonal antibody.\u003c\/p\u003e\n\n\u003cp\u003eFourteen patients (52%) had previously received treatment with an anti-GD2 monoclonal antibody. Thirteen patients had not received previous treatment with the GD2-directed monoclonal antibody because they did not have approved indications for its use.\u003c\/p\u003e\n\n\u003cp\u003eFor MYCN status, 7 patients (26%) had amplification, 5 (19%) had gain, 10 (37%) had normal status, and 5 (19%) had unknown status.\u003c\/p\u003e\n\n\u003cp\u003eFor sites of disease involvement:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eBone: 21 patients (78%)\u003c\/li\u003e\n\u003cli\u003eBone marrow: 12 patients (44%)\u003c\/li\u003e\n\u003cli\u003eLymph nodes: 11 patients (41%)\u003c\/li\u003e\n\u003cli\u003eAbdomen: 4 patients (15%)\u003c\/li\u003e\n\u003cli\u003eParavertebral area: 7 patients (26%)\u003c\/li\u003e\n\u003cli\u003eThorax or pleura: 2 patients (7%)\u003c\/li\u003e\n\u003cli\u003eLiver: 1 patient (4%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBefore infusion, 18 patients (67%) had an MIBG score of 7 or lower, and 9 patients (33%) had an MIBG score higher than 7. Before enrollment, all patients had disease resistance to at least two lines of treatment, with a range of two to six lines.\u003c\/p\u003e\n\n\u003cp\u003eOne patient in the phase 2 trial had received GD2-CART01 during complete remission at the end of first-line therapy. Of the 26 patients with relapsed or refractory disease, 24 had active, stage 4, metastatic disease at screening before treatment. Six of these patients had bulky disease.\u003c\/p\u003e\n\n\u003ch2 id=\"manufacturing\"\u003eMaking the Treatment for Each Patient\u003c\/h2\u003e\n\u003cp\u003eGD2-CART01 was manufactured successfully in all patients. No failure to generate GD2-CART01 was observed.\u003c\/p\u003e\n\n\u003cp\u003eThe median total number of CAR-positive T cells at the end of production was 2×10⁹ ± 1.4×10⁹ cells per kilogram, with a range of 0.7 to 6.9×10⁹. The median viability was 90.5 ± 3.7%, with a range of 82.2 to 96.1%. The median transduction efficiency was 72.4 ± 9.9%, with a range of 50.8 to 87.3%.\u003c\/p\u003e\n\n\u003cp\u003eTransduction efficiency means the percentage of cells that successfully received the new genetic instructions. Because production yielded multiple doses of cells for each patient, 11 patients received multiple infusions. Each patient could receive up to four infusions.\u003c\/p\u003e\n\n\u003cp\u003eThe retrovirus encoding the construct iCasp9.2A.GD2.CD28.4-1BB.zeta is approved for clinical use and has been described previously.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety Results: Side Effects and Toxic Effects\u003c\/h2\u003e\n\u003cp\u003eNo dose-limiting toxic effects were reported in the phase 1 trial. The recommended dose of 10×10⁶ CAR-positive T cells per kilogram was determined for the phase 2 portion of the trial.\u003c\/p\u003e\n\n\u003cp\u003eCytokine release syndrome (CRS) was one of the most common drug-related adverse events. CRS is a condition in which immune cells release large amounts of inflammatory chemicals into the blood. CRS was observed in 20 of 27 patients (74%) after the first infusion.\u003c\/p\u003e\n\n\u003cp\u003eThese CRS events were grade 1 or 2 in 19 of 20 patients (95%), meaning they were mild. Grade 3 CRS developed in only 1 patient after the first infusion, and it rapidly resolved after administration of tocilizumab. Tocilizumab is a drug that blocks the inflammatory signal interleukin-6.\u003c\/p\u003e\n\n\u003cp\u003eSerum levels of interferon-γ, interleukin-6, tumor necrosis factor α, and interleukin-10 were monitored in all patients. The researchers observed a correlation between significantly higher levels of circulating cytokines and the development and grade of cytokine release syndrome.\u003c\/p\u003e\n\n\u003cp\u003eCentral neurotoxic effects did not develop in any of the patients. Peripheral neurotoxic effects or pain occurred in 6 patients, all grade 1 or 2.\u003c\/p\u003e\n\n\u003cp\u003eSevere hematologic toxic effects (effects on blood cells) developed in all patients. These were induced by lymphodepletion and were sustained after GD2-CART01 infusion. The hematologic toxic effects included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eAnemia: grade 1 or 2 in 8 patients, grade 3 in 19 patients\u003c\/li\u003e\n\u003cli\u003eNeutropenia: grade 4 in all 27 patients\u003c\/li\u003e\n\u003cli\u003eThrombocytopenia: grade 1 or 2 in 1 patient, grade 3 in 4 patients, grade 4 in 19 patients\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eFor abnormal laboratory values, elevated alanine aminotransferase level, aspartate aminotransferase level, or both occurred in 13 patients at grade 1 or 2 and in 7 patients at grade 3. Elevated bilirubin level occurred in 3 patients at grade 1 or 2 and in 1 patient at grade 3. Electrolyte abnormalities occurred in 4 patients at grade 1 or 2 and in 2 patients at grade 3.\u003c\/p\u003e\n\n\u003cp\u003eFor miscellaneous events, a Clostridium difficile infection occurred in 1 patient at grade 3. Rash occurred in 3 patients at grade 1 or 2. Dysuria (painful urination) occurred in 2 patients at grade 1 or 2. One patient had a grade 4 brain hemorrhage.\u003c\/p\u003e\n\n\u003cp\u003eGrade 3, transient hepatic toxic effects (liver effects) developed in seven patients after infusion. In five of these patients, hepatic toxic effects were present before enrollment or before GD2-CART01 infusion and transiently worsened with the development of cytokine release syndrome. In one of the other two patients, a clinically relevant hepatic infiltration of disease was present and led to grade 3 toxic effects on activation of GD2-CART01. The other patient had grade 3 hepatic toxic effects 3 weeks after infusion of GD2-CART01, after resolution of cytokine release syndrome. These toxic effects were attributed to other hepatotoxic drugs that she was receiving.\u003c\/p\u003e\n\n\u003cp\u003eThe side-effect profile of multiple infusions was similar to the side-effect profile of a single infusion.\u003c\/p\u003e\n\n\u003ch2 id=\"suicide\"\u003eThe Safety Switch: How the Suicide Gene Worked\u003c\/h2\u003e\n\u003cp\u003eOne patient received two infusions of rimiducid. Rimiducid is a dimerizing agent intended to induce caspase 9 and destroy the transferred GD2-CART01 cells. This patient received rimiducid after an altered state of consciousness developed. However, the diagnostic workup revealed a brain hemorrhage as the causative event.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers evaluated the kinetics of GD2-CART01 over time in the patient who received rimiducid. They observed a sharp decrease in the level of circulating GD2-CART01 4 hours after infusion of the dimerizing agent. This decrease was sustained after the second infusion.\u003c\/p\u003e\n\n\u003cp\u003eAfter 6 weeks, the researchers detected a new expansion of GD2-CART01. The levels remained elevated at subsequent follow-up and were still detectable 30 months after infusion. The patient continued to have a complete response.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers then evaluated whether GD2-CART01 cells that re-expanded could derive from a subpopulation of cells that had lost sensitivity to rimiducid. GD2-CART01 cells collected at week 8 were exposed in vitro to rimiducid for 96 hours. This exposure produced a remarkable decrease in the number of CAR-positive T cells.\u003c\/p\u003e\n\n\u003ch2 id=\"expansion\"\u003eHow the CAR T Cells Grew and Survived in the Body\u003c\/h2\u003e\n\u003cp\u003eGD2-CART01 cells were detected in vivo by flow cytometry in 26 of 27 patients (96%). Flow cytometry is a laboratory method that counts and sorts individual cells.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers evaluated the correlation between the dose levels tested in phase 1 and the peak GD2-CART01 level in peripheral blood. They used both flow cytometry and droplet digital polymerase-chain-reaction (PCR) assay. Overall, peak expansion was observed in the second week after infusion on flow cytometry. The droplet digital PCR signal anticipated this peak by almost 1 week.\u003c\/p\u003e\n\n\u003cp\u003eGD2-CART01 persisted for at least 3 months in 75% of the evaluable patients and for more than 2 years in 2 children. The median persistence was 3 months, with a range of 1 to 30 months. GD2-targeted CAR T cells were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion.\u003c\/p\u003e\n\n\u003cp\u003eIn patients who received a second infusion, assessment of GD2-CART01 persistence after the first dose was terminated at the time of the second dose infusion. This termination occurred regardless of the circulating levels detected. The magnitude of expansion, expressed as an area under the curve, was 329.8 ± 165.7.\u003c\/p\u003e\n\n\u003cp\u003eExpansion of GD2-CART01 differed between patients who had a response to treatment and those who did not. The mean peak level of GD2-CART01 and the area under the curve in patients with a response were 157.95 ± 97.35 cells per cubic millimeter and 436.0 ± 229.0, respectively. In patients who did not have a response, these values were 70.38 ± 17.90 cells per cubic millimeter and 224.4 ± 126.6, respectively.\u003c\/p\u003e\n\n\u003cp\u003eAfter expansion, a predominance of CD8-positive CAR-positive cells was detected in peripheral blood and was maintained at all time points. CD4-positive CAR-positive cells also expanded and were detectable. For both CD4-positive CAR-positive and CD8-positive CAR-positive cells, the phenotype showed a strong prevalence of central and effector memory subpopulations. Central memory CD4-positive cells showed prolonged persistence.\u003c\/p\u003e\n\n\u003cp\u003eGD2-CART01 cells were detected in bone marrow up to 2 years after infusion. They were detected in the cerebrospinal fluid (the fluid around the brain and spinal cord) in five patients up to 12 weeks after infusion.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers did not observe any difference in bone marrow infiltration by GD2-CART01 between patients with a response and those without a response. The response group included six patients who had a complete response in the bone marrow. The non-response group included six patients who did not have a complete response in the bone marrow and three patients who had relapse in the bone marrow after infusion.\u003c\/p\u003e\n\n\u003cp\u003eGD2-CART01 cells that persisted long term did not show a relevant expression of exhaustion markers. Exhaustion markers are signs that immune cells have become worn out.\u003c\/p\u003e\n\n\u003cp\u003eAt the end of production, GD2-CART01 cells in the four patients with low in vivo expansion were characterized by a significantly higher proportion of terminally differentiated CD4-positive effector memory cells re-expressing CD45RA. Low in vivo expansion was defined as a peak of expansion less than 5% in peripheral blood. This proportion was higher than in the products of patients with higher in vivo expansion.\u003c\/p\u003e\n\n\u003ch2 id=\"response\"\u003eTreatment Responses: How Well It Worked\u003c\/h2\u003e\n\u003cp\u003eSeventeen children had a response to the treatment, for an overall response of 63%. Nine patients had a complete response, and 8 had a partial response.\u003c\/p\u003e\n\n\u003cp\u003eFive of 27 patients (19%) had stable disease, and 5 of 27 patients (19%) did not have a response. A total of 17 of 27 patients (63%) had an objective response.\u003c\/p\u003e\n\n\u003cp\u003eIn the entire cohort, the MIBG score decreased from a mean of 13 (range, 0 to 72) to 8.\u003c\/p\u003e\n\n\u003ch2 id=\"survival\"\u003eSurvival Results\u003c\/h2\u003e\n\u003cp\u003eAmong the patients who received the recommended dose, the 3-year overall survival was 60%. The 3-year event-free survival was 36%.\u003c\/p\u003e\n\n\u003cp\u003eOverall survival means the percentage of patients still alive at that time point. Event-free survival means the percentage of patients who remained alive without a relapse, progression, or other defined event.\u003c\/p\u003e\n\n\u003ch2 id=\"special\"\u003eThree Patients With an Unusual and Encouraging Course\u003c\/h2\u003e\n\u003cp\u003eIn three patients (Patients 18, 42, and 44), the researchers observed a peculiar clinical course. All three patients had a reduction in MIBG-positive lesions that was consistent with a partial response after the first infusion.\u003c\/p\u003e\n\n\u003cp\u003eTwo of them (Patients 18 and 42) received additional infusions of GD2-CART01. One then had stable disease, and a deeper partial response developed in the other.\u003c\/p\u003e\n\n\u003cp\u003eIn the subsequent follow-up, the three patients had persistently stable disease in the long term, although no other therapy was administered. All three patients had a negative positron-emission tomographic scan. The researchers noted that the durability of these remissions will be informative.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat These Findings Mean for Patients\u003c\/h2\u003e\n\u003cp\u003eThe use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect.\u003c\/p\u003e\n\n\u003cp\u003eFor families facing relapsed or refractory high-risk neuroblastoma, these results offer a meaningful signal of hope. This group of children had a very low probability of recovery with subsequent treatments before this trial. The long-term survival in this situation is approximately 5 to 10%.\u003c\/p\u003e\n\n\u003cp\u003eIn this trial, 63% of patients had an objective response. Among patients who received the recommended dose, 60% were alive at 3 years and 36% were alive without an event at 3 years.\u003c\/p\u003e\n\n\u003cp\u003eThe safety switch worked as designed. In the one patient in whom it was activated, the transferred cells were rapidly eliminated. The cells later re-expanded, and the patient continued to have a complete response.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers also found that higher expansion of GD2-CART01 in the blood was associated with response to treatment. Patients with a response had a mean peak level of 157.95 cells per cubic millimeter, compared with 70.38 cells per cubic millimeter in patients without a response.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, no central neurotoxic effects developed in any patient. This was a key concern that the suicide gene was designed to address.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\u003cp\u003eThis was a small, single-center, phase 1–2 trial with 27 patients. Small trials cannot prove that a treatment is better than another treatment. They can show that a treatment is feasible, safe, and worthy of further study.\u003c\/p\u003e\n\n\u003cp\u003eThe trial did not include a comparison group. Without a comparison group, researchers cannot be certain how much of the benefit is due to the treatment itself.\u003c\/p\u003e\n\n\u003cp\u003eSevere hematologic toxic effects developed in all patients. These effects were induced by lymphodepletion and were sustained after GD2-CART01 infusion. Patients receiving this treatment need close monitoring of their blood counts.\u003c\/p\u003e\n\n\u003cp\u003eSome patients had hepatic toxic effects, and in some cases these were attributed to other hepatotoxic drugs or to disease infiltration of the liver. This makes it difficult to attribute every liver effect to GD2-CART01 alone.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers noted that the durability of the remissions in the three patients with an unusual course will be informative. Longer follow-up is needed to understand how long responses last.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eWhat Patients and Families Should Know\u003c\/h2\u003e\n\u003cp\u003eGD2-CART01 is an investigational therapy. It was tested in a clinical trial, and it is not yet a standard treatment option. Families interested in this approach should ask their treatment team about available clinical trials.\u003c\/p\u003e\n\n\u003cp\u003eThe trial enrolled children and young adults between 1 and 25 years of age. All patients had high-risk neuroblastoma that had relapsed or that had not responded to first-line treatment.\u003c\/p\u003e\n\n\u003cp\u003eBefore receiving GD2-CART01, patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. This step is required to make room for the CAR T cells.\u003c\/p\u003e\n\n\u003cp\u003eFamilies should expect that side effects can occur. The most common drug-related side effect was cytokine release syndrome, which occurred in 74% of patients. In 95% of those cases, it was mild. Severe blood cell shortages occurred in all patients.\u003c\/p\u003e\n\n\u003cp\u003eFamilies should also know that the treatment includes a built-in safety switch. If dangerous side effects occur, doctors can activate this switch to eliminate the transferred cells.\u003c\/p\u003e\n\n\u003cp\u003ePatients in this trial could receive up to four infusions. Eleven patients received multiple infusions. The side-effect profile of multiple infusions was similar to that of a single infusion.\u003c\/p\u003e\n\n\u003cp\u003eQuestions families may want to ask their care team include:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003eIs my child eligible for a GD2-CAR T-cell clinical trial?\u003c\/li\u003e\n\u003cli\u003eWhat tests are needed before treatment, such as MIBG scans and bone marrow tests?\u003c\/li\u003e\n\u003cli\u003eWhat side effects should we watch for after infusion?\u003c\/li\u003e\n\u003cli\u003eHow long will my child need to be monitored after treatment?\u003c\/li\u003e\n\u003cli\u003eWhat options are available if the treatment does not work?\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is GD2-CART01 and how does it work?\u003c\/h3\u003e\n\u003cp\u003eGD2-CART01 is an investigational CAR T-cell therapy made from a patient's own T cells. It reprograms them to recognize and attack cells carrying the GD2 molecule, which neuroblastoma cells have in high levels. It also includes a built-in safety switch that doctors can activate to eliminate the transferred cells if dangerous side effects occur. It is not yet a standard treatment option.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible for this trial?\u003c\/h3\u003e\n\u003cp\u003eThe trial enrolled children and young adults aged 1 to 25 years with high-risk neuroblastoma that had relapsed or had not responded to first-line treatment. In the phase 2 portion, patients with metastatic disease and MYCN amplification could enroll after first-line treatment, even if they had a complete response. All patients had disease resistant to at least two prior lines of treatment.\u003c\/p\u003e\n\u003ch3\u003eWhat side effects occurred with GD2-CART01?\u003c\/h3\u003e\n\u003cp\u003eCytokine release syndrome occurred in 20 of 27 patients (74%), but it was mild in 19 of those 20 (95%). Severe blood cell shortages developed in all patients due to lymphodepleting chemotherapy. No central neurotoxic effects occurred. Other side effects included liver enzyme elevations, rash, and one brain hemorrhage. Multiple infusions had a similar side-effect profile to a single infusion.\u003c\/p\u003e\n\u003ch3\u003eHow well did the treatment work in this trial?\u003c\/h3\u003e\n\u003cp\u003eSeventeen of 27 patients (63%) had an objective response, including 9 complete responses and 8 partial responses. Among patients who received the recommended dose, 3-year overall survival was 60% and event-free survival was 36%. This was a small, single-center trial without a comparison group, so these results cannot prove the treatment is better than another treatment.\u003c\/p\u003e\n\u003ch3\u003eWhat is the safety switch and did it work?\u003c\/h3\u003e\n\u003cp\u003eThe safety switch is a built-in suicide gene called inducible caspase 9. If dangerous side effects occur, doctors can give a drug called rimiducid to activate the switch and destroy the transferred cells. In one patient who received it, the cells dropped sharply within 4 hours. The cells later re-expanded, and the patient continued to have a complete response.\u003c\/p\u003e\n\u003ch3\u003eWhat does 3-year overall survival of 60% mean?\u003c\/h3\u003e\n\u003cp\u003eAmong patients who received the recommended dose, 3-year overall survival of 60% means that 60% of those patients were still alive three years after treatment. Event-free survival of 36% means 36% were alive without relapse, progression, or another defined event. These figures come from a small trial of 27 patients and need confirmation in larger studies.\u003c\/p\u003e\n\u003ch3\u003eWhat should families expect during treatment?\u003c\/h3\u003e\n\u003cp\u003eBefore receiving GD2-CART01, patients receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide to make room for the CAR T cells. Side effects can occur, most commonly cytokine release syndrome, which was mild in most cases. Severe blood cell shortages occurred in all patients, so close monitoring of blood counts is needed. Patients could receive up to four infusions.\u003c\/p\u003e\n\u003ch3\u003eMy child has relapsed high-risk neuroblastoma — when should we seek a second opinion about CAR T-cell therapy?\u003c\/h3\u003e\n\u003cp\u003eRelapsed or refractory high-risk neuroblastoma has a long-term survival of approximately 5 to 10% with subsequent treatments, so families may want independent review before committing to a plan. GD2-CART01 is investigational and not yet a standard option; it was tested in 27 children, with a 63% objective response and, at the recommended dose, 60% overall survival at 3 years. A second opinion can confirm eligibility, prior GD2 antibody treatment, MIBG score, and whether a clinical trial fits. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma NEJM 2023\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e F. Del Bufalo, B. De Angelis, I. Caruana, G. Del Baldo, M.A. De Ioris, A. Serra, A. Mastronuzzi, M.G. Cefalo, D. Pagliara, M. Amicucci, G. Li Pira, G. Leone, V. Bertaina, M. Sinibaldi, S. Di Cecca, M. Guercio, Z. Abbaszadeh, L. Iaffaldano, M. Gunetti, S. Iacovelli, R. Bugianesi, S. Macchia, M. Algeri, P. Merli, F. Galaverna, R. Abbas, M.C. Garganese, M.F. Villani, G.S. Colafati, F. Bonetti, M. Rabusin, K. Perruccio, V. Folsi, C. Quintarelli, and F. Locatelli, for the Precision Medicine Team–IRCCS Ospedale Pediatrico Bambino Gesù.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e The New England Journal of Medicine, 2023;388:1284-95. DOI: 10.1056\/NEJMoa2210859.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c\/strong\u003e ClinicalTrials.gov number NCT03373097.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Funded by the Italian Medicines Agency and others.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919012577436,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-a-new-car-t-cell-therapy-for-children-with-hard-to-treat-neuroblastoma-results-of-a-27-patient-trial-hero.png?v=1793341280","url":"https:\/\/diagnosticdetectives.com\/es\/products\/a-new-car-t-cell-therapy-for-children-with-hard-to-treat-neuroblastoma-results-of-a-27-patient-trial","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}