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Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR 

This article originally appeared on our sister site, 

One-year post-transplant data in patients who underwent treatment with Gamida Cell's omidubicel showed sustained clinical benefits with the therapy as demonstrated by significant reduction in infectious complications. The findings were presented by Mitchell Horwitz, MD, professor of medicine at Duke Cancer Institute, at the 

Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR (2022 Tandem Meetings)

, held in Salt Lake City, Utah, and virtually April 23-26, 2022. 

The findings also showed a reduction in non-relapse mortality and no significant increase in relapse rates with omidubicel at 23% compared with UCBT at 18%.

Investigators concluded that hematopoietic stem cell transplantation (HSCT) with omidubicel resulted in rapid hematopoietic recovery, reduced rates of infection, and no increase in graft versus host disease rates compared with standard UCBT.

There was a continued trend toward improvement of overall survival with omidubicel at 73% compared with UCBT at 60%.

The overall and sustained clinical benefit of omidubicel makes the drug an important addition to options for allogeneic HSCT, investigators said.

“In allo-HSCT, early engraftment and lower infections are the key predictors of long-term success for patients,” Julian Adams, PhD, CEO of Gamida Cell, said in a statement.

“We are encouraged by the continuous positive and sustained results from patients involved in the phase 3 trial of omidubicel, now 1-year out from treatment. These results provide promising rationale that omidubicel could become a compelling treatment option for patients in need of an allo-HSCT transplant,” Adams said.

The company initiated a rolling biologics license application (BLA) submission for omidubicel in the first quarter of 2022 and is on-track to complete submission of all modules of the BLA in the second quarter. In total, the company presented 2 oral and 6 poster presentations at the conference.

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell transplant for individuals with 

. It has been granted breakthrough status and orphan drug designation by the FDA.

Additionally, omidubicel is being evaluated in a phase 1/2 clinical study in individuals with severe aplastic anemia.

It is an investigative therapy and the efficacy and safety profiles have not been established by the FDA or other health authorities.

Gamida cell has been developing NAM-enabled cell therapies, which are designed to enhance the number and functionality of target cells for individuals with hematological and solid cancers and other serious diseases.

NAM-enabled technology enables investigators to enhance, expand, and metabolically modulate multiple cell types, including natural kicker and stem cells, with appropriate growth factors to maintain the cells’ active phenotype and potency.

Gamida Cell presents updated one-year post-transplant follow up data from phase study of omidubicel at 2022 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR Tandem Meetings. News release. Gamida Cell. April 27, 2022. https://investors.gamida-cell.com/news-events/press-releases/news-release-details/gamida-cell-presents-updated-one-year-post

1-Year Data on Omidubicel Shows Sustained Benefits, Reduced Infection Rates

Data from ZUMA-7, a multicenter phase 3 trial, demonstrated statistically significant and clinically relevant improvements in event-free survival (EFS) and response rates in patients with relapsed/refractory large B-cell lymphoma (LBLC) treated with axicabtageneciloleucel (axi-cel) versus second-line standard of care (SOC) chemoimmunotherapy.

The findings, presented at the Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR (2022 Tandem Meetings), held in Salt Lake City, Utah, and virtually April 23-26, 2022, suggest that axi-cel should be considered second-line SOC for r/r LBLC.

The data presented included findings from 359 patients who were randomly assigned to receive either axi-cel (n=180) or SOC (n=179). Participants, of whom 74% had primary refractory disease, had a median age of 59. The primary end point was event-free survival, and secondary end points included objective response rate and overall survival.

Treatment with axi-cel met the primary end point, with EFS significantly longer at 24.9 months in the axi-cel group compared with SOC (8.3 months vs 2 months, 

<.0001). In addition, EFS Kaplan-Meier estimates were 41% and 16%, respectively, and objective response rates (ORR) and complete response (CR) rates were higher in the axi-cel group compared with SOC (ORR: 83% vs 50%, odds ratio: 5.31 [95% CI, 3.1-8.9; 

 <.0001]; CR: 65% vs 32%). Median overall survival, evaluated as an interim analysis, was not reached for axi-cel vs 35.1 months for SOC (HR 0.730; 

=.027). Notably 56% of patients in the SOC arm received crossover treatment with axi-cel off-protocol.

Progression-free survival (PFS) was also superior in the axi-cel group, with median PFS 14.7 months in the axi-cel cohort compared with 3.7 months in the SOC cohort.

“This intent to treat PFS curve compares favorably to the modified intent to treat PFS curve from ZUMA-1, suggesting that efficacy of axi-cel in a second line setting may be superior to efficacy seen in a third or later line,” primary investigator Frederick Locke, MD, of Moffitt Cancer Center, said during the data presentation.

In terms of safety, 91% (axi-cel) and 83% (SOC) of patients reported Grade 3 or higher treatment-emergent adverse events (TEAEs), with 1 and 2 patient treatment-related deaths occurring in each group, respectively. Grade 3 or higher cytokine release syndrome and neurologic events ccurred in 6% and 21% of the axi-cel group, with no grade 5 events recorded.

Notably, of the 180 participants randomized to axi-cel, 170 (94%) ultimately received definitive therapy compared with 36% of the SOC arm.

Overall, axi-cel demonstrated a more than 4-fold greater median EFS, 2.5-fold greater 2-year EFS, and 2-fold greater CR rate compared with SOC.

Locke FL, Miklos DB, Perales MA, et al. Primary Analysis of Zuma‑7: A Phase 3 Randomized Trial of AxicabtageneCiloleucel (Axi-Cel) Versus Standard‑of‑Care (SOC) Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma. Presented at: Presented at: the 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022.

The analysis of data from ZUMA-7 demonstrated significant efficacy for axi-cel over second-line standard treatment.  

ZUMA-7 Axi-Cel Superiority Calls for Treatment Paradigm Shift in R/R LBLC 

 This article was previously published by our sister site,

A match-adjusted comparative analysis of axicabtagene ciloleucel (Yescarta; axi-cel) in ZUMA-5 trial (NCT03105336) and tisagenlecleucel (Kymriah; tisa-cel) in ELARA (NCT03568461) demonstrated similar outcomes in patients with follicular lymphoma who underwent treatment with either cell therapy. The findings were presented at the 

, held in Salt Lake City, Utah, and virtually April 23-26, 2022.

“Tisa-cel and axi-cel have both been evaluated in pivotal phase 2 clinical trials with registrational intent—ELARA and ZUMA-5, respectively—which included patients with greater than or equal to 2 prior lines of therapy and both trials demonstrated high overall response rates [ORRs] and complete responses [CRs],” Michael Dickinson, MD, said during a presentation of the data. Dickinson is lead of the aggressive lymphoma disease group within Clinical Hematology at Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia.

“Given this clinical context, as well as promising 12-month progression-free and overall survival [OS] data, and because head-to-head comparisons between CAR T-cell products are unlikely to occur, we performed an indirect comparison of these 2 clinical trials and their CAR T interventions. The objectives of this study were to indirectly compare efficacy and safety outcomes between tisa-cel and axi-cel in relapsed or refractory follicular lymphoma using matching adjusted, indirect comparison.”

To conduct the analysis, investigators adjusted the population using individual patient-level data, using what Dickinson described as factors of convenience. “[Investigators of] both ZUMA-5 and ELARA have reported clinically relevant factors…these factors were reasonably reflective [of real-world] patients in that they were in both primary analyses and how clinicians think about prognostic factors for real-world refractory lymphoma.”

The weighting and match analysis included the following factors: age, sex, ECOG performance status, Ann Arbor tumor staging, follicular lymphoma international prognostic index score, tumor burden, number of prior lines of therapy, prior autologous stem cell transplant (ASCT), and progression of disease in 24 months. Patients treated with tisa-cel in ELARA were matched to the average baseline characteristics from aggregated summary data of those who received axi-cel in ZUMA-5.

Two analyses were performed. The primary analysis compared included patients from ELARA who received infusion and did not have exposure to bridging chemotherapy with comparable patients from ZUMA-5. The sensitivity analysis compared those in ELARA with and without exposure to bridging chemotherapy with patients from ZUMA-5.

“ELARA differed from ZUMA-5 in that it allowed bridging chemotherapy prior to CAR T-cell therapy,” Dickinson said. “We know from other studies, particularly in the large cell lymphoma setting, this may select for patients with poorer prognosis disease.”

Of note, Dickinson said investigators used a data cutoff of March 20, 2020, for ZUMA-5 and a March 29, 2021, data cutoff for ELARA. Efficacy-evaluable patients were defined as those with at least 12 months of follow-up.

Once balanced populations were achieved, investigators compared binary outcomes including ORR, CR, and safety, as well as an analysis of progression-free survival (PFS) and OS using weighted Cox proportional hazards model for hazard ratio estimation.

The primary analysis included 50 patients from ELARA and 84 patients from ZUMA-5. The ORRs after weighting were 92.59% vs 94.05% (

 < .05) and the CRs were 77.45% vs 79.76%, respectively. Dickinson noted that these results were comparable to the results observed before weighting which showed ORRs of 90% vs 94.05% and CRs of 70% vs 79.76%, among those treated with tisa-cel and axi-cel respectively.

The PFS was also comparable between the 2 agents. After weighting, the median PFS for those who received tisa-cel was not reached (NR; 95% CI, NR-NR) vs not reached (95% CI, 23.54-NR) with axi-cel (HR, 0.90; 95% CI, 0.39-2.06; 

 = .81). Prior to weighting investigators noted a hazard ratio of 1.02 (95% CI, 0.52-1.99).

OS analyses were also similar in the primary analysis with a hazard ratio of 0.33 (95% CI, 0.07-1.57) after weighting compared with 0.45 (95% CI, 0.13-1.59) prior to weighting.

The safety analysis was conducted among 53 patients from ELARA and 124 patients from ZUMA-5. Those who received tisa-cel had lower rates of cytokine release syndrome (CRS), corticosteroid and tocilizumab use for CRS, and overall incidence of neurologic events compared with those who received axi-cel.

Specifically, the rate of any-grade CRS, corticosteroid use, tocilizumab use, and any-grade neurological events among those who received tisa-cel were 45.52%, 2.63%, 9.59%, and 8.75%, respectively. Among patients treated with axi-cel these rates were 78.23%, 15.32%, 45.16%, and 56.45%, respectively. In terms of grade 3 events, no patients who received tisa-cel experienced grade 3 CRS compared with 6.45% of patients who received axi-cel. Further, only 0.29% of patients who received tisa-cel had a grade 3 neurologic event compared with 15.32% of patients who received axi-cel.

In an efficacy evaluation which included patients who received bridging therapy in ELARA (n = 90), results were also comparable in terms of efficacy to patients who received axi-cel in ZUMA-5 (n = 124). After weighting the ORR was 89.77% among those who received tisa-cel vs 94.05% among those who received axi-cel. The CR rates were 75.05% and 79.76%, respectively.

In terms of survival data, the median PFS for those who received tisa-cel was not reached (95% CI, 19.45-NR) vs not reached (95% CI, 23.53-NR) for those who received axi-cel (HR, 1.13; 95% CI, 0.60-2.15). These results were comparable to those observed prior to weighting in which the hazard ratio was 1.35 (95% CI, 0.79-2.32).

The weight-adjusted OS analysis showed that tisa-cel was significantly better than axi-cel with an HR of 0.23 (95% CI, 0.07-0.70) compared with 0.56 (95% CI, 0.21-1.52) prior to weighting.

“We’d like to be cautious of this result, given the short follow-up of ELARA and the earlier data cutoff from ZUMA-5,” Dickinson noted.

In terms of safety, 97 patients from ELARA were compared with 124 patients from ZUMA-5. Results were similar to those reported in the primary analysis. The median follow-up for safety was 17 months in ELARA and 15 months in ZUMA-5.

The rate of any-grade CRS, corticosteroid use, tocilizumab use, and any-grade neurological events among those who received tisa-cel were 47.01%, 4.89%, 13.71%, and 7.96%, respectively. Among patients treated with axi-cel these rates were 78.23%, 15.32%, 45.16%, and 56.45%, respectively. In terms of grade 3 events, CRS was reported among 0.06% of patients in ELARA compared with 6.45% in ZUMA-5 and 0.97% of patients who received tisa-cel had a grade 3 neurologic event compared with 15.32% of patients who received axi-cel.

“Future studies using long term follow-up data from both trials or real-world data will be important for comparisons of the efficacy and safety of tisa-cel and axi-cel for the treatment of relapsed or refractory follicular lymphoma,” Dickinson said.

Dickinson M, Martinez-Lopez J, Jousseaume E, at al. Comparative efficacy and safety of tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) in relapsed/refractory follicular lymphoma (FL). Presented at: 2022 Transplantation & Cellular Therapy Meetings; April 23-26, 2022. Abstract 77.

Tisa-cel was associated with a more favorable safety profile in the analysis. 

Axi-Cel, Tisa-Cel Have Comparable Efficacy in Follicular Lymphoma, Analysis Shows

The latest findings from the ZUMA-5 clinical trial (NCT03105336) show a durable effect for treatment of patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) with axicabtagene ciloleucel (axi-cel; Yescarta).

, held in Salt Lake City, Utah, and virtually April 23-26, 2022, demonstrated a continued high response rate and activity in patients with relapsed/refractory FL and MZL. 

In patients with FL, investigators reported a median duration of response (DOR) of 38.6 months and that 57% of efficacy-eligible patients had an ongoing response at the data cutoff of March 31, 2021. In this population, median progression-free survival (PFS) was nearly 40 months, and median overall survival (OS) was not reached (NR). The overall response rate (ORR) was 94% (79% complete response [CR] rate).

In patients with MZL, after a median of 24 months, efficacy outcomes appeared to improve with longer follow-up, with median DOR and OS not yet reached. Median PFS was 17.3 months. Investigators reported that half of the patients with MZL had an ongoing response at data cutoff. The ORR was 83% in patients with MZL (63% CR rate).

According to the ZUMA-5 trial protocol, an updated efficacy analysis was conducted when 80 or more treated patients with FL had more than 24 months of follow-up. A total of 110 efficacy-eligible patients were analyzed: 86 patients with FL and 24 patients with MZL. Safety data were reported for all 149 patients treated with axi-cel (124 patients with FL and 24 patients with MZL).

“In the primary analysis of [ZUMA-5; n = 104], the ORR was 92% and investigators reported a 74% CR rate after a 17.5-month median follow-up,” study author Julio C. Chavez, MD, an associate member in the Lymphoma Section of the Department of Malignant Hematology at Moffitt Cancer Center, in Tampa, Florida, said. “Here, we report updated clinical and pharmacologic outcomes from ZUMA-5 with 2 or more years of follow-up.” Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of R/R large B-cell lymphoma and follicular lymphoma, both after more than 2 lines of systemic therapy.

Among patients with FL who progressed after less than 2 years after initial chemoimmunotherapy (POD24; n = 49), median DOR was 38.6 months. Median DOR was not reached in those without POD24 (n = 29). Median PFS was 39.6 months and NR in patients with and without POD24, respectively. Median time to next treatment (TTNT) was 39.6 months in all eligible patients with FL. Investigators reported that median OS was NR.

“Across key subgroups, long-term PFS rates in patients with FL were generally consistent,” Chavez said. Similarly, despite the limited sample size of the MZL population, the PFS rate at 12 months appeared to be consistent among key subgroups, including those patients treated with a prior Bruton tyrosine inhibitor.

Turning to safety, Chavez said the most common grade 3 or higher adverse events (AEs) were neutropenia (33%), decreased neutrophil count (28%), and anemia (25%). Seven percent of patients (6% in FL and 8% in MZL) experienced grade 3 or worse cytokine release syndrome (CRS) and 19% of patients (15% in FL and 36% in MZL) reported neurologic events. Chavez noted that most CRS cases (120 of 121) and neurologic events (82 of 87) of any grade resolved by data cutoff. Thirty-four percent of patients reported grade 3 or higher cytopenias 30 days or more post infusion (33% in FL and 36% in MZL), and the most common cytopenia reported was neutropenia in 29% of patients (27% in FL and 36% in MZL).

After data cutoff, grade 5 AEs occurred in 6 patients: 1 due to COVID-19 (unrelated), 1 COVID-19 pneumonia (related to axi-cel), 1 progressive multifocal leukoencephalopathy (related to axi-cel) and 2 cases of sepsis (both unrelated).

Chavez noted robust chimeric antigen receptor T-cell expansion in patients with FL and ongoing responses at 24 months than in patients who had relapsed. Pharmacokinetic findings were similar in patients with MZL.

Chavez said the long-term follow up in ZUMA-5 showed substantial and continued benefit of the CAR T-cell therapy. “Axi-cel maintained a manageable safety profile with no new safety signals,” he concluded.

Neelapu SS, Chavez JC, Sehgal AR, et al. Long-Term Follow-up Analysis of Zuma-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL). Presented at: the 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022. Abstract 75.

In this population, median progression-free survival was nearly 40 months.

Durable Response Seen With Axi-Cel in Non-Hodgkin Lymphoma

The allogeneic CD19-directed CAR natural killer T (CAR-NKT)–cell therapy KUR-502 elicited a 6-month complete response (CR) rate of 29% for patients with relapsed or refractory (R/R) B-cell malignancies, according to updated interim findings from the phase 1 ANCHOR study (NCT03774654) presented at the 

Interim findings from the dose escalation study were available for 7 patients, 5 with B-cell non-Hodgkin lymphoma (NHL) and 2 with B-cell acute lymphoblastic leukemia (ALL). The overall response rate (ORR) with KUR-502 across patients was 57%, which was assessed 4 to 6 weeks post-infusion by Lugano criteria. This consisted of a CR rate of 43% and a partial response (PR) rate of 14%. An additional patient experienced stable disease (SD) for a disease control rate (DCR) of 71%. Additionally, there were 2 responses observed following relapse on a prior autologous CAR T-cell therapy.

"Despite the small numbers, we've shown that adoptive transfer of allogeneic CD19 CAR-NKT cells is feasible and safe. We've seen some significant responses, even at the low levels we've tested so far. Importantly, 2 out of 4 responses were in patients in whom prior autologous CAR T-cell therapy had failed," lead investigator Carlos Ramos, MD, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Center for Cell and Gene Therapy, said during a presentation of the results. "We definitely need to treat more patients. I believe this first-in-human clinical evaluation of allogeneic CAR-NKT cells suggests they are a promising platform for off-the-shelf cancer immunotherapy."

KUR-502 consists of allogeneic NKT cells that have been engineered using a retrovirus to co-express a CD19-specific CAR, IL-15, and short hairpin RNA (shRNA) that works to downregulate beta-2 microglobulin (B2M) and CD74, which are HLA class I and class II molecules, respectively. On top of these engineered qualities, NKT cells are also monomorphic CD1d-restricted and Vα24-invariant, making them non-alloreactive. These attributes are thought to prevent the risk of graft-vs-host disease (GVHD) with an "off-the-shelf" product.

For KUR-502, NKT cells were collected by leukapheresis from 1 HLA-unmatched donor, transduced, and then expanded ex vivo for 14 days. The final product had 99.8% NKT purity (0.04% were T cells) and was cryopreserved. There was a 2869-fold expansion in cells, providing enough CAR-NKT cells from 1 healthy donor for the full phase 1 study, according to Ramos.

The open-label phase 1 study enrolled patients into 2 cohorts: 1 for those with non-ALL B-cell malignancies (n = 5) and the other for those with ALL (n = 2). Treatment was administered in the outpatient setting and those enrolled received either dose level (DL) 1 (n = 5), which was 1 x 10

 NKT-CAR+ cells, or DL2 (n = 2), which consisted of 3 x 10

. Prior to administration of KUR-502, patients received 3 daily doses of lymphodepleting chemotherapy with fludarabine (30mg/m

In patients with NHL (n = 5), responses consisted of 2 CRs, 1 PR, and 1 SD, for an ORR in this cohort of 60% and a DCR of 80%. There were 2 CRs that persisted for more than 6 months, including 1 that remained ongoing at 34 weeks. In those with ALL (n =2), there was 1 CR with incomplete hematologic recovery seen at 6 weeks. There were no SDs or PRs in this group, for an ORR and DCR of 50%. 

The responses seen following relapse on autologous CAR T-cell therapy consisted of 1 CR and 1 PR, both in patients with diffuse large B-cell lymphoma. One was experienced at DL1 and the other at DL2. The patient with a CR was at 57 year old woman treated with DL2 of KUR-502. She had previously received axicabtagene ciloleucel (Yescarta), tafasitamab (Monjuvi), and polatuzumab vedotin (Polivy). This CR had persisted for almost 9 months at the time of the analysis, Ramos noted.

No cases of GVHD or neurotoxicity syndrome were observed, and the incidence of cytokine release syndrome (CRS) was low with only 3 events seen in 2 patients both in the ALL cohort. All CRS events were deemed grade 1 in severity. The most frequently observed adverse events were nausea and grade 3/4 hematologic toxicities, that were most likely related to the lymphodepletion chemotherapy.

“Encouraging data from the interim update of the ANCHOR study further support the promising efficacy and favorable safety profile of KUR-502 in heavily pretreated patients with hematological malignancies,” Dan Lang, MD, president of Athenex Cell Therapy, the company developing the treatment, said in a statement. “It is exciting to see the therapeutic benefit of our CAR-NKT cell therapy persists as the ANCHOR study matures, particularly in patients who have already progressed on autologous CAR-T therapy. We intend to collect additional patient data as we expand the study to include more sites and look forward to providing another update later this year.”

When possible, patients underwent core biopsies for further assessment. These typically took place 2 to 5 weeks post-infusion of KUR-502. In biomarker analyses, beyond 3 hours post-infusion, investigators could no longer detect CAR-NKTs cells in the peripheral blood in the first 3 patients NHL treated with KUR-502; however, expansion was seen at higher doses.

"Expansion of these cells in peripheral blood is quite limited," said Ramos. "Although we can detect their expansion immediately after infusion, even at low dose levels, we can only detect these cells in the peripheral blood by flow cytometry and later by Q-PCR in patients with higher doses infusion, suggesting a dose relationship."

Follow-up from the study will remain ongoing and additional patients will be recruited. The study hopes to enroll 48 participants. As the dose continues to be escalated, dose level 3 of 1 x 10

 will also be administered, to continue to search for a maximum tolerated dose and dose limiting toxicity (NCT03774654).

For more coverage of the Tandem Meetings 2022, 

Ramos CA, Courtney AN, Robinson SN, et al. Allogeneic NKT Cells Expressing a CD19-Specific CAR in Patients with Relapsed or Refractory B-Cell Malignancies. Presented at: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Accessed April 25, 2022. 

https://tandem.confex.com/tandem/2022/meetingapp.cgi/Paper/19125

KUR-502 elicited promising response rates for patients with relapsed or refractory B-cell malignancies in a phase 1 study. 

NKT Cell Therapy KUR-502 Effective for B-Cell Malignancies

A T-allo10 cell infusion appears safe and well-tolerated in children and young adults with hematologic malignancies when manufactured from a haploidentical donor, according to preliminary phase 1/1b data presented in a poster at the 

Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR

 (2022 Tandem Meetings), held in Salt Lake City, Utah, and virtually April 23-26, 2022.

Investigators at Stanford University are conducting the single center, non-randomized, non-controlled open-label phase 1/1b trial (NCT04640987) in order to evaluate whether their T-cell immunotherapy, T-allo10, can result in better patient outcomes by improving immune reconstitution and graft-versus-leukemia (GvL) immune response after αβ+ T-cell and CD19+ B-cell depleted (αβdepleted) hematopoietic stem cell transplantation (HSCT), without increasing the risk of graft versus host disease (GvHD).

“Allogeneic HSCT is the only cure for most pediatric patients with acute leukemia,” investigators reported. “However, its use has been limited by the availability of [human leukocyte antigen] HLA matched donors. Recently, αβdepleted HSCT has enabled a significant broadening of the use of HLA-partially matched related and unrelated donors. Still, the rate of viral reactivations (~50 %) and leukemic relapse (25-30 %) after αβdepleted-HSCT remains high, mostly because of the poor immune reconstitution due to extensive ex vivo αβ T-cell depletion and use of pre-HSCT serotherapy.”

The T-allo10 product is made using donor CD4+ T cells that include regulatory type 1 T (Tr1) cells differentiated in vitro, which are specific for the host alloantigens and suppress host-reactive TCRαβ+ T cells that cause GvHD. It also includes polyclonal naive and memory TCRαβ+ T cells that can respond to pathogens and tumor antigens.

Investigators hypothesize that administering the T-allo10 infusion in patients who have already undergone αβdepleted-HSCT could accelerate immune reconstitution “by providing a source of TCRαβ+ T cells and supporting the generation of donor-derived naive T cells, therefore reducing the risk of infections and leukemic relapse, without increasing the risk of GvHD.”

The phase 1 primary end point is recommended phase 2 dose of T-allo10 at 3 different escalating doses (1x10

 cells/Kg) to be administered within 35 +/-7 days after αβdepleted-HSCT. Phase 1b primary end points included the following: safety, as defined by the absence of dose-limiting toxicities (DLT) 28 days following the T-allo10 infusion (given at the recommended phase 2 dose) administered after αβdepleted-HSCT; and improvement of IR, defined as an increased proportion of patients who reach the threshold of 50 CD3

The study protocol consisted of a fully myeloablative conditioning regimen prior to αβdepleted-HSCT, as well as GvHD prophylaxis of anti-thymocyte globulin (ATG), with no post-HSCT pharmacologic GvHD prophylaxis. Patients then proceeded to T-allo10 infusion as long as there was no evidence of myeloid engraftment and no signs of grade II acute GvHD requiring > 0.5 mg/Kg of steroids or grade III/IV acute GvHD.

At the time of the poster presentation, investigators had enrolled 7 patients in the study (3 female, 2 male, 1 transgender male), and 6 of the 7 had received an infusion of T-allo10. The median age at enrollment was 13.95 years (range, 1.5–24).

To date, investigators have observed no DLT, defined as grade IV acute GvHD or grade 3/4 treatment-related adverse events. Compared with 25 historical controls, preliminary data support a more rapid post-HSCT immune reconstitution of CD3

 T cell in the first patient treated with 3x10

/Kg T-allo10 cells, and 2 patients achieved the primary phase 1b efficacy end point.

“Our preliminary data show that the T-allo10 cell infusion is safe and well-tolerated when

manufactured from a haploidentical donor,” investigators concluded. “Antigen-specific Tr1 cells contained in the T-allo10 drug product are detectable in the recipients and traceable by TCR clonotype analysis.”

1. Bertaina A, Bacchetta R, Shyr D, et al. Phase 1/1b study of T-allo10 infusion after HLA-partially matched aβdepleted-HSCT in children and young adults with hematologic malignancies: preliminary results. Poster presented at: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Accessed April 22, 2022. 

https://tandem.confex.com/tandem/2022/meetingapp.cgi/Paper/19113

The treatment seeks to improve immune reconstitution and graft-versus-leukemia immune response without increasing the risk of GvHD in children and young adults with hematologic malignancies.

T-allo10 Cell Infusion After Haploidentical HSCT Is Safe, Well-Tolerated, Prelim Data Show

Initial data from a phase 1 trial examining the feasibility of third-party, donor-derived natural killer (NK) cells in patients with relapsed or refractory acute myeloid leukemia (R/R AMLY) or myelodysplastic syndrome demonstrated good safety and cell persistence, according to findings presented at the 

Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR (2022 Tandem Meetings)

Recognizing the challenges associated with personalized donor-derived cell therapies, the investigator-initiated study, led by Sumithira Vasu, MD, of Ohio State University Comprehensive Cancer Center, worked to identify third-party NK cell donors in order to establish an off the shelf NK cell bank using membrane-bound interleukin-21 feeder cells and cryopreserved NK cells.

Goals of the open-label, dose-escalation study include determining the persistence of ex-vivo expanded, off the shelf, third-party donor cells; characterization of in vivo expansion of the cells and any differences based on conditioning regimen; and determination of immunophenotype and function of expanded cells. The study has a target enrollment of 30 participants that include adults with R/R AML who have received 1 to 3 prior lines of therapy.

Vasu and colleagues presented data on 6 treated patients, 3 of whom were in cohort 1 and were <60 years old and received fludarabine 30 mg/m

/day on days -6 to –2; and 3 of whom were in cohort 2, were ≥60 years old and received fludarabine 30 mg/m

/day (days -5 to -2) and decitabine 20 mg/m

/day (days -6 to -2) followed by infusion of HLA-mismatched NK cells 3 times per week for 6 doses at the first dose level of 1x107 cells/kg/dose on days 0, 2, 4, 6, 8, and 10. Notably, 1 patient withdrew prior to NK cell infusion. 

Overall, NK cell infusion was well-tolerated in the remaining 5 patients, all of whom received the total 6 doses over 2 weeks. One report of a cytokine release-type syndrome was reported in 1 patient, while 1 other proceeded to allogeneic hematopoietic stem cell transplant. Notably, no adverse events, including infusion-related reactions, neurotoxicity, or graft versus host disease were reported.

Following analysis with flow cytometry, the investigators concluded that NK cell persistence and expansion in vivo was superior in cohort 1 which underwent lymphodepletion with the fludarabine 30 mg/m

/day regimen. Two of 3 patients in cohort 1 reached over 50% donor NK cells between day 0 and day 14 as a proportion of all mononuclear cells in peripheral blood.

“Cryopreserved, third-party donor-derived NK cells are safe and feasible in relapsed/refractory AML patients, and at this first dose level, completely HLA-mismatched NK cells can persist and expand to high levels in vivo,” concluded Vasu and colleagues.

For more coverage of the Tandem Meetings 2022, click here. 

Vasu S, Sharma. N, Wall SA, et al. A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Third-Party Donor-Derived Natural Killer Cells for Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome. Presented at: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Abstract 276.

Preliminary findings from the phase 1 clinical trial demonstrate good cell persistence and expansion in vivo.  

Off the Shelf NK Cell Therapy Feasible in R/R Acute Myeloid Leukemia, Myelodysplastic Syndrome 

The first 4 real-world patients treated with betibeglogene autotemcel (beti-cel; LentiGlobin; bluebird bio) for transfusion-dependent β-thalassemia (TDT) exhibited tolerability that was consistent with what investigators observed during clinical trials, and none of the 4 individuals required red cell transfusion as far as 332 days post-infusion treatment.

Andreas Kulozik, Dr. med, PhD, medical director of the clinic for Pediatric Oncology, Hematology, Immunology and Pulmonology, at University Medical Center for Children and Adolescents in Heidelberg, Germany, presented these findings in a poster during the 

The real-world data support the recently published results

 from a phase 3 study (HGB-207; NCT02906202) in which most adult and pediatric patients with transfusion-dependent β-thalassemia and a non–β0/β0 genotype treated with beti-cel achieved 

"I think the main take is that gene therapy really is a curative option for these patients who do not have an allogeneic stem cell donor," Kulozik told 

 in a video interview. "My personal feeling is, if in the long run gene therapy...shows itself to be safe, it might even be superior to allogeneic bone marrow transplantation or peripheral blood cell transplantation because we do not run into the problems of [graft versus host disease]."

The FDA is set to review additional data on beti-cel, as well as bluebird bio’s cerebral adrenoleukodystrophy (CALD) candidate elivaldogene autotemcel (eli-cel), in a pair of meetings on June 9 and 10, after the agency moved in January to 

“Gene therapies are complex, potentially transformative treatment options for those living with severe genetic diseases, and we all share a responsibility to be diligent for patients as we progress this novel field,” Andrew Obenshain, chief executive office of bluebird bio, said in a statement at the time.

 “We look forward to continuing to work with the FDA on its ongoing reviews of beti-cel and eli-cel, and to bringing these therapies to patients with β-thalassemia and CALD in the US later this year.”

Kunz J, Roth E, Greil J, et al. The first real-world experience with betibeglogene autotemcel (beti-cel) gene therapy treatment for transfusion-dependent β-thalassemia (TDT). Poster presented at: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Accessed April 21, 2022. https://tandem.confex.com/tandem/2022/meetingapp.cgi/Paper/19562

Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogeneautotemcelgenetherapy for non–β0/β0 genotype β-thalassemia. 

. 2022; 386:415-427. doi: 10.1056/NEJMoa2113206

bluebird provides update on FDA review timelines for betibeglogeneautotemcel (beti-cel) for beta-thalassemia and elivaldogeneautotemcel (eli-cel) for cerebral adrenoleukodystrophy (CALD). News release. bluebird bio. January 18, 2022. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-provides-update-fda-review-timelines-betibeglogene

The real-world data support the recently published results from a phase 3 study, which showed most patients achieved transfusion independence.

Real-World Experience With Beti-cel for Patients With TDT Is Consistent With Trials

Building on previously reported 12-month follow-up data from Group C of the HGB-206 study (NCT02140554) of lovotibeglogene autotemcel (bb1111; lovo-cel; LentiGlobin) for the treatment of sickle cell disease (SCD), investigators shared additional 24-month post-treatment data in a poster presented at the 

A lovo-cel infusion resulted in clinically meaningful health-related quality of life (HRQoL) benefits that sustained up to 2 years after administration, including near-complete resolution of the painful vaso-occlusive events (VOEs) that characterize SCD, investigators reported.

Lovo-cel comprises the autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which generates an antisickling hemoglobin, HbA

. The ongoing phase 1/2 HGB-206 study is evaluating the efficacy and safety of lovo-cel for patients with SCD, as well as its effect on incidence of VOEs, frequent hospitalizations, and patient-reported quality of life (QoL) outcomes.

Patients included in Group C were ≥ 12 – ≤ 50 years with a genotype of either β

. All individuals reported a history of severe VOEs, defined as ≥ 4 severe VOEs in 2 years before informed consent, as well as failure of or intolerance to hydroxyurea.

Study investigators gathered patient-reported outcomes at baseline using PRO Measurement Information System (PROMIS)-57, and then every 6 months through month 24. QOL categories spanned physical, mental, and social, and included 7 domains: Depression, Anxiety, Pain Interference, Fatigue, Sleep Disturbance, Physical Function, and Satisfaction with Participation in Social Roles. Additionally, patients were asked to rate their pain intensity on a scale of 1-10.

Baseline PROMIS-57 data were available for 25 of the 35 patients in Group C. Of these 25, the median age was 25 year (range, 19–38) and 60% were male. Patients in the overall population (n = 25) were divided into 2 subgroups per each domain depending on whether their baseline assessment was “better or near” or “worse” than what is considered the US population norm, which measured a standardized T-score of 50 for all 7 domains and a rating of 2.6 for Pain Intensity.

“Meaningful within-patient change was calculated as a function of change in group means and defined as ≥ 5-point change for all domains and ≥ 2-point change for Pain Intensity,” investigators reported.

Patients reported meaningful change in mean difference for all 7 PROMIS-57 domains except Anxiety, as well as in the Pain Intensity score. The QoL benefits kicked in early and sustained through month 24 post-infusion. Patients who reported “worse” baselines scores compared with the population norm related improvements in all 7 domains 6 to 24 months post-infusion. The greatest improvements were seen in the Pain, Fatigue, and Physical Functioning domains.

Overall, investigators concluded that “these findings may reflect the resolution of severe VOEs in all patients up to and beyond 24 months, with improvements to patient QoL not yet observed in the SCD treatment landscape to-date.”

The development of bluebird bio’s lovo-cel has been 

, as the company hit another bump in the road in December 2021 when the FDA placed the program on 

 following a report of persistent anemia in an adolescent patient. The pause marked the second clinical hold for the program, the first of which was lifted in June 2021 after the company demonstrated that its lentiviral vector was not associated with patients developing acute myeloid leukemia and myelodysplastic syndrome. Under the FDA directive, the company is able to continue conducting follow-up of previously treated patients, which comprises the Tandem Meetings data presented here.

“While the partial hold is in place, we intend to continue planned follow-up on previously treated patients from HGB-206 and HGB-210 and plan to enroll and treat new adult patients with lovo-cel through study HGB-210 to further characterize the efficacy and safety of lovo-cel for patients with SCD and to continue to advance the field of gene therapy,” bluebird bio’s chief medical officer Richard Colvin, MD, said in a statement at the time.

Lovo-cel is currently being evaluated in the phase 3 HGB-210 study (NCT04293185) and previous positive efficacy data has been presented from the phase 1/2 HGB-206 study (NCT02140554).

 The FDA has granted the gene therapy orphan drug, fast track, regenerative medicine, and rare pediatric disease designations.

1. Walters M, Tisdale J, Mapara M, et al. Sustained improvements in patient reported quality of life up to 24 months post-treatment with lentiglobin for sickle cell disease (bb1111) gene therapy. Presented at: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Accessed April 21, 2022. 

2. bluebird bio Announces Partial Clinical Hold for Patients Under 18 in Sickle Cell Gene Therapy Clinical Program. News release. bluebird bio. December 20, 2021. 

https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-partial-clinical-hold-patients-under-18

3. Walters MC, Thompson AA, Kwiatkowski JL, et al. Resolution of Serious Vaso-Occlusive Pain Crises: Results from the ongoing phase 1/2 HGB-206 group C study of lentiglobin for sickle cell disease (SCD; bb1111) gene therapy. Presented at: 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; Held virtually February 8-12, 2021. Abstract 13.

The greatest improvements were seen in the Pain, Fatigue, and Physical Functioning domains.

LentiGlobin for Sickle Cell Disease: 24-Month Follow-Up Yields Sustained QOL Outcomes

Axicabtagene ciloleucel (axi-cel; Yescarta) CAR T-cell therapy as first-line treatment for patients with high-risk large B-cell lymphoma (LBCL) produced encouraging responses, according to updated phase 2 ZUMA-12 (NCT03761056) data presented during the 

2022 Transplantation & Cellular Therapy Meetings

In 37 evaluable patients, the objective response rate (ORR) in the study was 89% (95% CI, 75%-97%) with complete responses (CRs) in 78%. Partial responses (PRs) were observed in 11% of the evaluable population, while 8% has stable disease (SD), and only 3 had progressive disease (PD).

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that already has FDA approval for the treatment of adults with relapsed or refractory LBCL and relapsed/refractory follicular lymphoma following at least 2 prior lines of therapy. ZUMA-12 is the first study to assess treatment with axi-cel in the first-line setting.

“Patients with high-risk large B cell lymphoma have poor outcomes, including lower response rates and poor overall survival. In addition, patients with early disease resistance as assessed by dynamic PET scan, after first-line chemoimmunotherapy have an increased risk of death,” said Sattva Neelapu, MD, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, and deputy department chair, Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX during a presentation at the 2022 Transplantation and Cellular Therapy Meetings.

Based on the unmet medical need for therapies to improve outcomes in high-risk LBCL, ZUMA-12 was created. The study is a phase 2, multicenter, open-label, single-arm study. At the 2022 TCT Meetings, Neepalu presented results on efficacy, safety, pharmacokinetics, and pharmacodynamics.

Per the study design, patients included in ZUMA-12 were those with high-grade B-cell lymphoma with 

 translocations or have an International Prognostic Index (IPI) score of ≥ 3. All patients must be 18 years of age or older with an ECOG performance score of 0 or 1, and their interim PET scan should show a Deauville score of 4 or 5 after 2 cycles of anti-CD20 mAb plus an anthracycline-containing regimen.

“Following enrollment and leukapheresis, patients could receive optional non-chemotherapy bridging, which could have included either corticosteroids or localized radiation. And once the product has been generated, they received standard [fludarabine] conditioning followed by a single infusion of axi-cel,” explained Neelapu about ZUMA-12 treatment.

The fludarabine conditioning was administered at 30 mg/m2 via intravenous (IV) infusion with cyclophosphamide 500 mg/m2 IV on days -5, -4, and -3. Axi-cel was administered at 2 x 106 CAR T cells/kg on day 0.

The primary end point of the ZUMA-12 study is CR rate assessed by investigators per Lugano 2014 classification. Secondary end points of the study include ORR, duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), safety, and CAR T cells in blood and cytokine levels in serum.

Of the 42 patients enrolled, 40 were treated with condition chemotherapy and axi-cel. The patients had a median age of 61 years (range, 23-86), and were 68% male. In terms of disease characteristics, 95% of patients in the study has stage III or IV disease, 63% had an ECOG score of 1, and 100% had at least 1 prior systemic therapy. FISH testing assessed by investigator showed that 40% of patients had double- or triple-hit, and 25% were double- or triple-hit per central laboratory assessment. Also, the IPI score was ≥ 3 for 78% of patients, and 48% had a Deauville score of 4, while 53% had a Deauville score of 5.

The median follow-up for response in the evaluable population was 15.9 months (range, 6.0-26.7), with 62% of patients having been followed for ≥ 12 months. As of the data cutoff date, 73% of patients were having an ongoing response to axi-cel. The median time to response was 1.0-month (range, 0.9-6.8). Of the 11% who initially had a PR, 16% eventually converted to a PR. Moreover, 3% of those whose initial response was SD converted to a CR.

In the overall population (n = 40), the ORR was 90% (95% CI, 76%-97%) with a CR rate of 80% (95% CI, 64%-91%. Notably, CRs were consistent across all subgroup populations. The median DOR was not reached, but at month 12, the DOR rate was 80.8% (95% CI, 59.3%-91.6%).

All survival outcomes had not been reached by the time of data cut off. At 12 months, the EFS rate was 72.5% (95% CI, 53.1%-84.9), the PFS rate was 74.6% (95% CI, 54.8%-86.7%, and the OS rate was 90.6% (95% CI, 73.4%-96.9%).

Any-grade treatment-emergent adverse events (TEAEs) occurred in all 40 patients in the study of which, 85% were grade 3 or higher. The most common grade ≥ 3 axi-cel-related TEAEs were neutrophil count decrease (53%), white blood cell count decrease (43%), anemia (30%), encephalopathy (15%), and platelet count decrease (15%).

Serious TEAEs were observed in 45% of patients. In 68% of patients, grade ≥ 3 cytopenias occurred, and 15% experienced grade ≥ 3 infections. Twelve of patients died due to either PD (10%), COVID-19 (3%), or septic shock (3%).

Cytokine release syndrome (CRS) occurred in all patients in the study, but only 8% experienced grade 3 CRS. The most common CRS-related symptoms observed were pyrexia (100%), hypotension (30%), chills (25%), and hypoxia (23%).

“Tocilizumab was administered in 63% of outpatients and corticosteroids in 35% of the patients for management of CRS, only one patient required vasopressors,” noted Neelapu. “The median time to onset of CRS was four days and the median duration was 6 days. There were no grade 4 grade 5 CRS events and all CRS events resolved as of the data cut off.”

Neurologic events of any grade were observed in 73% of patients, and these events were grade 3 for 23% and grade 2 for 38%. The most common symptoms associated with neurologic events in the study were confusional state (28%), encephalopathy (25%), and tremor (25%).

Regarding neurologic events, Neelapu stated: “The median time to onset was 9 days and the median duration was 7 days. There were 2 grade 4 neurological events both due to encephalopathy and both resolved. There were no grade 5 neurological events noted. As of the data cut off, there's 1 patient who has an ongoing grade 1 tremor.”

Finally, ZUMA-12 results were compared with results from ZUMA-1 (NCT02348216), in which axi-cel was evaluated as third-line treatment for patients with LBCL.

“We observed a higher frequency of CCR7-positive, CD45RA-positive T cells in ZUMA-12 versus in ZUMA-1. Within the product, 35% of these T cells were of this phenotype on ZUMA-12 versus only 14% on ZUMA-1. And this was a phenotype that was previously associated with a favorable newer PK profile and better clinical efficacy,” said Neelapu.

The greater frequency of CCR7-positive, CD45RA-positive T cells observed in ZUMA-12 was associated with greater CAR T-cell expansion, which signals improved T-cell fitness in the first-line setting. Based on the collective findings, Neelapu et al., axi-cel may be beneficial to patients exposed to fewer prior therapies as well as those with high-risk LBCL.

Neelapu SS, Dickinson M, Munoz JL, et al. Primary analysis (PA) of Zuma-12: A phase 2 study of axicabtagene ciloleucel (Axi-Cel) as first-line therapy in patients (Pts) with high-risk large b-cell lymphoma (lbcl). Presented at. 2022 Transplantation and Cellular Therapy Meetings; April 23-26, 2022; Salt Lake City, UT. Abstract 12.

In 37 evaluable patients, the objective response rate in the study was 89% (95% CI, 75%-97%) with complete responses in 78%. 

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