Long term data from a phase 1/2 study (NCT04684940) of valoctocogene roxaparvovec (valrox) for the treatment of 

 demonstrated that although the treatment is efficacious up to 5 years post-treatment, Factor VIII expression did fall over the long-term, raising concerns over the one-time infusion’s treatment durability.

Investigators found that the 6 x 1013 vg/kg dose cohort (n = 7) experienced a 95% reduction in mean ABR from baseline to 5 years and a 96% reduction in mean annualized Factor VIII utilization from baseline to 5 years post-treatment. However, Factor VIII activity levels fell from treatment to 5-year follow-up as measured by both chromogenic substrate assay (CSA) and one-stage assay (OSA).

"The consistent and impressive bleed control in the majority of the study participants out to 5 years in this study, which is the longest duration of clinical experience for any gene therapy in hemophilia A, increases our understanding of the interplay between Factor VIII expression, ABR, and Factor VIII infusion rate as it relates to hemostatic efficacy," said principal investigator Michael Laffan, BMBCh, DM, FRCP, FRCPath, professor, Department of Immunology and Inflammation, Imperial College London, and Director, Hammersmith Hospital Haemophilia Centre, in a statement. "These data show that most of the study participants have not had a bleed or had to infuse Factor VIII in the last five years after one infusion of valrox, which has the potential to provide a treatment choice that addresses many of the unmet needs in hemophilia."

The highest dose cohort experienced a reduced mean ABR from 16.3 (median, 16.5) at baseline to 0.8 (median, 0.0) episodes per year among the 6 participants previously treated with FVIII prophylaxis (mean follow-up, 266.1 weeks [5.1 years]). In year 5, 86% (n = 6) of participants in the high dose cohort had no treated bleeds.

Gene Therapy for Hemophilia B Efficacious, Well-Tolerated

The lower dose cohort (n = 6), treated with 4 x 1013 vg/kg showed that a single infusion of valrox reduced mean ABR by 92% from 12.2 (median, 8.0) at baseline to 1.0 (median, 0.5) bleeding episodes per year (mean follow-up, 218.6 weeks [4.2 years]). In year 4, 50% (n = 3) of participants had no treated bleeds.

High dose cohort participants experienced a 96% reduction in mean annualized Factor VIII utilization from 135.6 (median, 136.5) to 5.2 (median, 0.1) infusions per year among the 6 participants previously treated with FVIII prophylaxis. Lower dose participants experienced a 95% reduction in mean annualized Factor VIII utilization from 142.8 (median, 155.8) to 7.8 (median, 1.4) infusions per year. Exogenous Factor VIII was used as treatment for bleeding, surgery or procedures, and as one-time prophylaxis during follow-up in both cohorts.

Participants in both cohorts continued to experience substantial decline in levels of endogenous Factor VIII expression as confirmed by both CSA and OSA assays. In the low dose cohort, Factor VIII expression decreased from a mean of 5.6 IU/dL (standard deviation [SD], 5.6) to a median of 4.8 IU/dL after 4 years via CSA and from a mean of 9.5 IU/dL (SD, 7.0) to a median of 7.5 IU/dL after 4 years via OSA. In the high dose cohort, Factor VIII expression decreased from a mean of 11.6 IU/dL (SD, 12.2) to a median of 8.2 IU/dL at 5 years via CSA and from a mean of 18.7 IU/dL (SD, 17.5) to a median of 15.7 IU/dL after 5 years.

As of the most recent year of observation, 6 participants in the high dose cohort were in the mild to moderate hemophilia range, and 1 participant was below the lower limit of quantification as measured by CSA. One participant was in the non-hemophilic range, 4 were in the mild range, and 1 was in the moderate range as measured by OSA. Four participants in the low dose cohort were in the mild to moderate hemophilia range, and 2 were below the lower limit of quantification as measured by CSA. All 6 were in the mild to moderate range as measured by OSA.

Valrox has continued to be well-tolerated, with no delayed-onset treatment related adverse events (AEs). All participants continue to remain off corticosteroids since the first year, none developed inhibitors to Factor VIII, and none withdrew from the study. Common AEs included short-lived infusion-associated reactions and transient, asymptomatic, and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae.

"We are optimistic that ABR may be maintained acceptably low through years 3, 4, and 5 after treatment with valrox in the GENEr8-1 study given the predictable, and not sudden or dramatic, change in Factor VIII expression in the later years following treatment in the Phase 1/2 study," added Hank Fuchs, MD, president, Worldwide Research and Development, BioMarin. "The data show excellent hemostatic efficacy in the 6e13 and 4e13 vg/kg dose cohorts, which is maintained into year 5 and 4, respectively. We look forward to sharing topline two-year data from all participants in the pivotal Phase 3 GENEr8-1 study in early 2022."

 from the phase 3 GENEr8-1 study (NCT03370913) which showed that participants treated with valrox experienced a significant, 84% reduced mean ABR (

 <.001) from baseline and a 99% reduced mean annualized Factor VIII utilization rate (

"The demonstrated bleed control at 52 weeks and beyond in this pivotal study supports our thesis that gene therapy can play an important role in the treatment of severe hemophilia A and potentially creates the possibility for a new treatment paradigm," said lead principal investigator Margareth C. Ozelo, MD, PhD, director, INCT do Sangue Hemocentro UNICAMP, University of Campinas, in another statement. "It is encouraging to see meaningful endogenous Factor VIII expression and decreases in bleeding and Factor VIII infusions for people in this study. These pivotal results contribute to the growing body of data to increase understanding of the safety and efficacy of gene therapy treatment over time."

The FDA previously rejected BioMarin’s biologics license application for valrox in August 2020, issuing a complete response letter that cited the need for additional durability data. The FDA requested 2-year follow-up data from the phase 3 study to confirm the durability of the treatment. The last patient in the study will complete 2 years of follow up study in November 2021.

On the European side, BioMarin resubmitted their marketing authorization application to the European Medicines Agency (EMA) in June 2021 after the EMA granted the company's request for accelerated assessment in May 2021. The agency had previously requested 52-week data from the phase 3 GENEr8-1 study. The EMA Committee for Medicinal Products for Human Use opinion is expected in the first half of 2022.

1. BioMarin announces oral presentation at ISTH 2021 Virtual Congress with 5 years of clinical data from ongoing phase 1/2 study of valoctocogene roxaparvovec in adults with severe hemophilia a, demonstrating continued, durable clinical benefit. News release. BioMarin. July 21, 2021. 

https://www.biospace.com/article/releases/biomarin-announces-oral-presentation-at-isth-2021-virtual-congress-with-5-years-of-clinical-data-from-ongoing-phase-1-2-study-of-valoctocogene-roxaparvovec-in-adults-with-severe-hemophilia-a-demonstrating-continued-durable-clinical-benefit/


2. BioMarin announces oral presentation of positive one-year results from phase 3 pivotal trial with valoctocogene roxaparvovec gene therapy in adults with severe hemophilia A at ISTH 2021 Virtual Congress. News release. BioMarin. July 19, 2021. https://investors.biomarin.com/2021-07-19-BioMarin-Announces-Oral-Presentation-of-Positive-One-Year-Results-from-Phase-3-Pivotal-Trial-with-Valoctocogene-Roxaparvovec-Gene-Therapy-in-Adults-with-Severe-Hemophilia-A-at-International-Society-on-Thrombosis-and-Haemostasis-ISTH-2021-Virtua
3. FDA turns down BioMarin's hemophilia A gene therapy. News release. BioMarin. August 19, 2020. Accessed July 27, 2021. https://www.biospace.com/article/fda-rejects-biomarin-s-hemophilia-a-gene-therapy/
4. BioMarin resubmits marketing authorization application (MAA) to European Medicines Agency for valoctocogene roxaparvovec to treat severe hemophilia A. News release. BioMarin. June 28, 2021. https://www.biospace.com/article/releases/biomarin-resubmits-marketing-authorization-application-maa-to-european-medicines-agency-for-valoctocogene-roxaparvovec-to-treat-severe-hemophilia-a/

Articles

A drop in endogenous Factor VIII expression was observed from treatment to 5-year follow-up despite continued demonstration of efficacy. 

Valoctocogene Roxaparvovec’s Treatment Durability in Hemophilia A in Question

This content originally appeared on our sister site, 

 We’re still looking at seizures, and we’re maybe seeing some of these behavior and executive improvements with fenfluramine. But we really need something beyond seizure control, right? We’ve got to try to get at that underlying SCN1A haploinsufficiency. And it’s exciting. I’m sure you’re as excited as I am to be involved with some of these other clinical trials that have either started or will be starting soon that are trying to get at some underlying disease-modifying approaches. It almost seems like science fiction to me, in the sense that 5 years ago I probably put my foot in my mouth and said to some families, “I just don’t see gene therapy in my lifetime.” I was having a hard time wrapping my head around what, at least I thought, was the conventional approach of gene editing. 

 That’s why we have these super-bright PhD people who have an interest in this area.

 I think that’s been very exciting to see develop.

 Exactly, and it’s exciting to think that it could extend to other pediatric epilepsy genetic diagnoses, not just Dravet syndrome. But right now, there’s a lot of focus on Dravet syndrome, and that’s obviously why we’re here. Maybe you could explain, for me and for our audience, this technique that’s the antisense oligonucleotide that’s in phase 1/2 clinical trial.

 Sure. What that is, it targets mRNA. In Dravet syndrome what happens is the pathogenic variant leads to degradation, nonsense mediated decay of this mRNA, so it can’t function to then make protein. What this antisense oligonucleotide does is it kind of forms this bridge and it prevents the degradation from happening, and so it restores normal NaV1.1 protein. It resolves that haploinsufficiency you see in Dravet syndrome and restores normal levels of protein. So with that, there’s a lot of excitement that that then targets the underlying pathogenesis. The hope is that it will not only improve seizures but also reduce the risk of SUDEP [sudden unexpected death in epilepsy], and it looks, at least in animal studies, that that might occur, and may also improve many of the other comorbidities, sort of attenuate the developmental concerns that we see, improve gait issues, behavior. So it’s very exciting.

 Absolutely. I get some questions from families who say, “Well, does my child’s mutation qualify?” This is not going in and fixing the variant your child may have, but rather is taking advantage of that working nonmutated copy, to basically tell it to do more, or to use the products of its labor in a more effective way that ultimately translates into, as you said, increased expression of that NaV1.1 channel. And in those animal models, it has done exactly that. When they look at the expression not only of the messenger RNA, but of the percentage increase in the sodium channel, it approximates that of an individual, or of a mouse in this case, who has two working copies of the SCN1A gene. Then there’s another, also equally brilliant, approach to use an adeno-associated virus, AAV technology, which conventionally has sometimes been used to insert the actual gene into the genome so that it does “fix” them. But the SCN1A gene is too large to be packaged in that virus.

So Encoded Therapeutics, [Inc] has devised this approach where a genetic promoter essentially binds to the working, nonmutated allele, the working SCN1A copy, and effectively tells it to produce more of this messenger RNA, which can then be translated into hopefully a working sodium channel, the NaV1.1 protein. It’s the same sort of end result, but a different way of getting there. Both of these approaches are either in early clinical trial or are going into clinical trial very soon, and so it is exciting to think about not only FDA-approved medications to treat seizures, but something that could get at the root cause. I think there’s a lot of interest, certainly from us as clinicians and our colleagues, but even more interest on the part of the patient community, because this is what they’ve been asking for, for so long.

. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming programs and other great content in your inbox. Thank you so much.

Videos

Joseph Sullivan, MD, and Elaine C. Wirrell, MD, discuss new developments for the treatment of Dravet syndrome beyond seizure control including gene editing and therapy.

Novel Therapies in Development for Dravet Syndrome

“We are very excited about new technologies coming in the processing world... I remember [5, 6 years ago] we tried to make things work with equipment that was designed for other purposes. Now we see equipment specifically for our needs. We're trying to bring that in to make processes more efficient, more robust, which also will lower the cost."

Mustang Bio presented positive data on MB-106, a CD20-targeted, autologous CAR T cell therapy for the treatment of high-risk B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL), at the European Hematology Association (EHA) 2021 Virtual Congress.

Investigators found that MB-106 yielded an overall response rate (ORR) of 93% (14 of 15) and a complete rate (CR) of 67% (10 of 15). The ORR was 91% (10 of 11) and CR was 82% (9 of 11) in patients with follicular lymphoma. As of EHA 2021, all patients achieving CR remained in remission. CAR T persistence was seen in all dosages. The treatment had an acceptable safety profile, with cytokine release syndrome (CRS) occurring in 6 patients (40%): 3 cases of grade 1 and 3 cases of grade 2.

 spoke with Knut Niss, PhD, chief technology officer, Mustang Bio, to learn more about the company’s approach to producing CAR T therapies. He also discussed upcoming changes to their processing facility that will further expedite production.

Mustang Bio announces updated interim phase 1/2 data for MB-106 CD20-targeted CAR T in patients with relapsed or refractory B-cell non-hodgkin lymphomas and chronic lymphocytic leukemia. News release. Mustang Bio. June 11, 2021. 

https://ir.mustangbio.com/News/news-details/2021/Mustang-Bio-Announces-Updated-Interim-Phase-12-Data-for-MB-106-CD20-Targeted-CAR-T-in-Patients-with-Relapsed-or-Refractory-B-cell-Non-Hodgkin-Lymphomas-and-Chronic-Lymphocytic-Leukemia/default.aspx

The chief technology officer of Mustang Bio discussed the company’s approach and future plans in CAR T production. 

Improving Efficiency in CAR T Cell Therapy Production

This content originally appeared on our sister site,

Findings from an interim analysis of the ongoing phase 1 BrainChild-01 trial (NCT03500991) suggest that repetitive locoregional infusion of HER2-specific CAR T cells did not induce any dose-limiting toxicities. Furthermore, the cells elicited clinical and correlative laboratory evidence of local central nervous system (CNS) immune activation in 3 pediatric patients with recurrent or refractory CNS tumors.

The clinical evidence included high concentrations of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 2 (CCL2) in the cerebrospinal fluid (CSF) and serum samples.

“This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients,” Nicholas Alexander Vitanza, MD, an assistant professor at the Ben Towne Center for Childhood Cancer Research, and a staff member of the Cancer and Blood Disorders Center, Brain Tumor Program, Apheresis, at Seattle Children’s, and coauthors, wrote in the study publication.

Although the integration of CAR T-cell therapy has provided a novel therapeutic modality to manage multiple hematologic malignancies, the utility of CAR T cells is not fully understood for pediatric patients with CNS tumors.

HER2 offers a valid target for CAR T-cell therapy in CNS tumors because it is widely expressed on a significant proportion of biologically diverse CNS tumors such as ependymoma, glioblastoma, and medulloblastoma, as well as CNS cancer stem cells. Moreover, HER2 is not expressed on normal CNS tissue.

Monoclonal antibodies, such as trastuzumab (Herceptin), are beneficial for patients with some HER2-expressing cancers but have limited activity in CNS tumors that require a therapy that crosses the blood-brain barrier. CNS tumors also harbor less HER2 expression compared with malignancies like breast cancer.

As such, directly administering HER2-directed therapy to the tumor site could be a lucrative strategy for patients with CNS tumors.

Preclinical data demonstrated that spacer length was correlated with improved activity of HER2-specific CAR T cells. Based on this, the single-institution BrainChild-01 trial used a medium-length spacer HER2CAR to evaluate repeated locoregional delivery of HER2-specific CAR T cells for pediatric patients with recurrent or refractory CNS tumors.

Following CAR T-cell manufacturing, patients were treated in the outpatient setting for up to 6 courses. Course 1 consisted of 3 weeks of a 1 x 107 dose of CAR T cells (DL1), followed by clinical evaluation in week 4. Course 2 consisted of 1 week of DL1 treatment, 2 weeks of a 2.5 x 107 dose of CAR T cells (DL2), followed by clinical and radiographic evaluation in week 4. Courses 3 through 6 retained the same dosing schedule at the highest tolerated dosing levels, which included 2 additional tiers: 5 x 107 [DL3] and 10 x 107 [DL4].

“The BrainChild-01 HER2CAR T-cell product was manufactured under a process designed to yield balanced numbers of CD4+ and CD8+ lentivirally transduced T cells exhibiting limited terminal differentiation with enrichment for the CAR+ population of cells mid-culture,” Vitanza and coauthors wrote.

The initial 3 patients were required to be from 15 to 26 years old. This age group is more capable of self-reporting neurologic changes compared with a younger patient population, so they were specifically used for the initial evaluation.

The first eligible 3 patients underwent apheresis and had CAR T-cell products that were in-line with release criteria. As such, the patients were assigned to the appropriate treatment arms: repeated locoregional CNS infusion into the CNS tumor or tumor cavity (arm A; n = 1) vs repeated locoregional CNS infusion into the ventricular system (arm B; n = 2).

All patients had undergone at least 3 prior tumor-directed surgical procedures, at least 1 prior irradiation, and at least 1 prior chemotherapy regimen. Additionally, all patients had presumed pediatric biology of their tumors.

A 19-year-old female patient enrolled on arm A was diagnosed with WHO grade III localized anaplastic astrocytoma. She had 1.95 x 109 total nucleated cells manufactured and 1.87 x 109 EGFRt+ CAR T cells manufactured. She received 6 doses of treatment.

Both patients enrolled on arm B were males with WHO grade III metastatic ependymoma. The first, a 16-year-old, had 3.2 x 109 total nucleated cells manufactured, 2.97 x 109 EGFRt+ CAR T cells manufactured, and received 9 doses of treatment. The second patient, aged 26, had 2.06 x 109 total nucleated cells manufactured, 1.87 x 109 EGFRt+ CAR T cells manufactured, and received 9 doses of treatment. The latter patient’s product in arm B had initial failure of viability screening, but with 2 additional manufacturing attempts, enough CAR T cells were generated to complete a minimum of 2 treatment courses.

The study was designed to primarily assess feasibility, safety, and tolerability, with assessment of CAR T-cell distribution and disease response as secondary objectives.

Patients experienced post-treatment symptoms. One patient who underwent imaging experienced radiographic evidence of treatment-mediated localized CNS immune activation.

Additional results showed that the most common adverse effects (AEs) observed in all patients were headache, pain at metastatic sites of spinal cord disease, and transient worsening of a baseline neurologic deficit. Additionally, the 2 patients on arm B experienced fever within 24 hours following infusion. These AEs were deemed possibly, probably, or definitely related to CAR T-cell therapy.

Systemic C-reactive protein elevation was also noted in all patients and overlapped with the timing of headaches and/or pain.

Regarding CSF cytokines and radiographic imaging, CAR T cells were not detected in any patient at any time point following infusion in CSF via flow cytometry or in peripheral blood via quantitative polymerase chain reaction. Non–CAR T cell populations of CD4+ and CD8+ T cells were detected in CSF after infusion.

Cytokines, including CXCL10, CCL2, granulocyte colony–stimulating factor, granulocyte-macrophage colony-stimulating factor, IFNα2, IL-10, IL12-p70, IL-15, IL1α, IL-6, IL-7, and tumor necrosis factor–α, were detected in the CSF following infusion. One patient also had elevated VEGF.

Additional studies are planned to evaluate the relationship between target antigen density and clinical toxicity and response.

With these findings, the trial is planned to enroll the broader age cohort of patients aged 1 to 26 years. Notably, the trial will include patients with diffuse midline glioma.

Two additional studies are also planned. BrainChild-02 (NCT03638167) will deliver EGFR-specific CAR T cells to pediatric patients with recurrent or refractory EGFR-positive CNS tumors. BrainChild-03 (NCT04185038) will deliver B7-H3–specific CAR T cells to pediatric patients with recurrent or refractory CNS tumors or diffuse intrinsic pontine glioma.

Gleaning the results of all 3 BrainChild studies, the investigators plan to use a multiplexed strategy to overcome tumor heterogeneity, which remains a challenge for drug development in this patient population, and antigen escape.

“Ultimately, the experience of the initial three patients treated on BrainChild-01 suggests that repeated locoregional HER2-specific CAR T-cell dosing might be feasible and that correlative CSF markers might be valuable in assessing on-target CAR T-cell activity in the CNS,” concluded Vitanza and coauthors.

Vitanza NA, Johnson AJ, Wilson AL, et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. 

 Published online July 12, 2021. Accessed July 20, 2021. doi:10.1038/s41591-021-0140

Encouraging results from the phase 1 BrainChild-01 trial were recently published.

HER2-Specific CAR T Therapy Shows Safety and Efficacy in Pediatric Tumors

CAR T-cell products vary in terms of efficacy and toxicity due to heterogeneity in their cellular and molecular features. Following treatment with axicabtagene ciloleucel (Yescarta; axi-cel) in patients with large B-cell lymphoma (LBCL), molecular response at day 7 might represent an early predictor of efficacy with this modality, according to results from a study published by 

Patients who were able to achieve a complete response (CR) to the treatment via positron emission tomography/computed tomography at 3 months of follow-up had frequencies of CD8 T cells expressing memory signatures that were 3-fold higher than those who achieved partial responses or progressive disease.

When sequencing cell-free DNA at day 7 following the infusion, molecular response was found to be significantly associated with clinical response (

 = .008). Moreover, a signature of CD8 T-cell exhaustion was linked (

 = 2.8 × 10−149) with a poor molecular response within this population.

“When we look at the characteristics of the infused CAR T cells, we found that samples from patients who were less responsive to treatment had exhausted T cells, whereas those who experienced CRs had T cells expressing ‘memory’ signatures,” Sattva Neelapu, MD, a professor in the Department of Lymphoma and Myeloma, of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, stated in a press release.2 “Additionally, 1 cellular signature of T-cell exhaustion was more commonly found in patients who exhibited a poor molecular response, and poor molecular response is generally associated with less-positive, long-term outcomes.”

Patients with LBCL who remain in either CR or PR at 3 months following treatment with an autologous CD19-targeted CAR T-cell therapy have been shown to have better outcomes than those who just achieve stable disease or who progress before this time point. In the context of B-cell leukemia, phenotypes within the apheresis product and CAR T-cell product have been identified as key cellular features associated with response. However, this has not been investigated in LBCL, nor has it been systemically evaluated using single-cell transcriptomics.

Investigators hypothesized that the heterogeneity of these kinds of CAR T products could contribute to interpatient variability in terms of efficacy and toxicity. To evaluate this further, a single-cell analysis was conducted on CAR T cells to evaluate gene expression profiles in cells that had been infused. Investigators collected CAR T cells from infusion bags from 24 patients with LBCL who had undergone treatment. From there, genetic profiles were compared with responses to treatment, as determined via a PET/CT scan 3 months following infusion.

Treatment-related adverse effects (TRAEs), such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), that are often associated with CAR T-cell therapies and can impede recovery. Additional findings indicated that a rare cell subgroup with monocyte-like transcriptional features were linked with high-grade ICANS (

“When we examined the infusion product, we found that a cell population with characteristics similar to myeloid cells, with a monocyte-like transcriptional signature, was associated with development of high-grade neurotoxicity,” Michael Green, PhD, an associate professor within Department of Lymphoma and Myeloma, Division of Cancer Medicine at MD Anderson Cancer Center, added in the release. “Detecting these cells may subsequently lead us to identify patients who would be at higher risk of developing neurotoxicity, allowing us to provide prophylactic treatment with agents that target the specific cellular features.”

These findings provide insight into patients who will either experience poor outcomes or TRAEs with CD19-targeted CAR T-cell products, allowing for treatment adjustments to increase efficacy and reduce toxicity.

“This study also tells us that some rare and unexpected cells identified by single-cell analysis could be biologically important,” Linghua Wang, MD, an assistant professor within the Department of Genomic Medicine, Division of Cancer Medicine at MD Anderson Cancer Center, added in the release. “Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results.”

1. Deng Q, Han G, Puebla-Osorio N, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. 

. 2020;26:1878–1887. doi:10.1038/s41591-020-1061-7.
2. Study identifies characteristics of infused CAR T cells associated with efficacy and toxicity in patients with large B-cell lymphoma. News release. The University of Texas MD Anderson Cancer Center. October 5, 2020. Accessed October 6, 2020. 

Heterogeneity in the cellular and molecular features of CAR T-cell products contributes to variation in efficacy and toxicity follow treatment with axicabtagene ciloleucel.

ctDNA Changes May Predict CD19-Targeted CAR T-cell Therapy Response in LBCL

Human chimeric antigen receptor (CAR) T CD19 (huCART19), a modified chimeric antigen receptor, was found to yield long-term, efficacious remissions in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to the results of a phase 1 study (NCT02374333) published in the 

Patients who had not previously received any CAR T-cell therapy experienced a complete response (CR)/ CR with incomplete count recovery (CRi) of 98% (n = 40/41) and 100% (n = 39/39) at day 28 following the infusion. All responders were minimal residual disease (MRD)–negative. In the retreatment cohort, the rate CR/CRi was 79% at day 28, with 86% of responders being MRD-negative. However, five patients did not have biologic response because B-cell aplasia was not established. One month following infusion, patients in the CAR T­–naïve arm had an overall response rate (ORR) of 98% vs 64% in the retreatment cohort. and after 1 and 2 years 74% and 58% remission rate respectively.

“These results show that [huCART19] is an encouraging option for retreatment in a difficult-to-treat population,” Shannon L. Maude, MD, PhD, an attending physician in the Cancer Center at CHOP and senior author of the study, said in a press release.2 “We are continuing to analyze the effectiveness of this approach in a phase 2 trial, which is ongoing.”

The open-label study enrolled 74 pediatric and young adults, from age 1 up to 29 years of age with either relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (BLL; n = 2). Investigators originally planned to administer a dose of 3 x 107 cells/kg with an acceptable range of 3 x 105 to 3 x 107 cells/kg with a maximum dose of 1.5 x 109 cells of huCART19 through an intravenous injection in patients who were 50 kg or more. Following an amendment to the base dose, the remaining 26 products were adjusted to 6 x 106huCART19 cells/kg with an acceptable range of 2 x 105 to 6 x 106 huCART19 cells/kg and a maximum dose of 5 x 108 huCART19 cells.

The study included 2 cohorts of patients who either had prior exposure or retreatment (B-ALL, n = 33) and patients who were CAR-naïve, without prior exposure 41 (B-ALL, n = 39; BLL, n = 2).

The primary end point of the study was safety and feasibility of huCART19 infusion, as well as duration of persistence. Key secondary end points included ORR at day 28, MRD-negative CR/CRi rate, event-free survival, OS, and an exploratory cytokine analysis.

The median follow-up was 21.2 months after infusion. Additional data from the study indicated patients in the CAR-naïve group experienced a 1-year relapse-free survival (RFS) rate of 84% (95% CI, 72-97) and a 2-year RFS rate of 74% (95% CI, 60-90), while the re-treatment arm had a 1- and 2-year RFS of 74% (95% CI, 56-97) and 58% (95% CI, 37-90), respectively. At 12 months, those who achieved CR/CRi with B-cell aplasia (n = 21) had a relapse-free survival rate of 74% (95% CI, 56%-97%). At 24 months, the RFS for this group was 58% (95% CI, 37%-90%). At 12 and 24 months, incidence of relapse was 24% (95% CI, 8%-44%) and 36% (95% CI, 15%-59%) respectively.

For patients who experienced a CR/CRi, 12 relapsed before undergoing additional therapy was received. Among this group, 6 were positive for CD19 cells, 4 were CD19-negative, and 2 had both positive and negative CD19 leukemic cells. At 6 months, patients who experienced B-cell aplasia had incidence of B-cell recovery 15% (95% CI, 6%-28%) in the CAR-naïve group and 58% (95% CI, 33%-77%) in retreatment group.

Some adverse effects (AEs) that patients experienced were cytokine release syndrome (CRS) occurring in 84% of patients, with 5 patients developing grade 4 effects. Neurologic toxicities occurred in 39% of patients that was of grade 3 (n=1) or grade 4 (n=1) and was fully resolved in all cases. Common serious AEs included CRS, febrile neutropenia, and encephalopathy. There were no treatment-related deaths noted by investigators during the study. All treatment-related AEs were reversible with the exception of persistent cytopenias past 8 weeks in 59% of the CAR-naïve cohort and 45% of the retreatment cohort.

“…The potential for improved persistence with huCART19, which may be associated with a decreased risk of relapse, warrants further study,” the authors of the study concluded.

1. Myers RM, Li Y, Barz Leahy A, et al. Humanized CD19-targeted chimeric antigen receptor (CAR) T Cells in CAR-naive and CAR-exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia. Published online ahead of print, June 22, 2021. 

. 2021. doi:10.1200/JCO.20.03458
2. CHOP researchers develop humanized CAR T-cell therapy that shows potential for patients with relapsed B-ALL. News Release. June 28, 2020. Accessed July 8, 2021. 

huCART19 is designed to yield longer remission rates for pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia.