24 research outputs found
Solar Effects on Tensile and Optical Properties of Hubble Space Telescope Silver-Teflon(Registered Trademark) Insulation
A section of the retrieved Hubble Space Telescope (HST) solar array drive arm (SADA) multilayer insulation (MLI), which experienced 8.25 years of space exposure, was analyzed for environmental durability of the top layer of silver-Teflon (DuPont) fluorinated ethylene propylene (Ag-FEP). Because the SADA MLI had solar and anti-solar facing surfaces and was exposed to the space environment for a long duration, it provided a unique opportunity to study solar effects on the environmental degradation of Ag-FEP, a commonly used spacecraft thermal control material. Data obtained included tensile properties, solar absorptance, surface morphology and chemistry. The solar facing surface was found to be extremely embrittled and contained numerous through-thickness cracks. Tensile testing indicated that the solar facing surface lost 60% of its mechanical strength and 90% of its elasticity while the anti-solar facing surface had ductility similar to pristine FEP. The solar absorptance of both the solar facing surface (0.155 plus or minus 0.032) and the anti-solar facing surface (0.208 plus or minus 0.012) were found to be greater than pristine Ag-FEP (0.074). Solar facing and anti-solar facing surfaces were microscopically textured, and locations of isolated contamination were present on the anti-solar surface resulting in increased localized texturing. Yet, the overall texture was significantly more pronounced on the solar facing surface indicating a synergistic effect of combined solar exposure and increased heating with atomic oxygen erosion. The results indicate a very strong dependence of degradation, particularly embrittlement, upon solar exposure with orbital thermal cycling having a significant effect
Pilot Study of Prophylactic Ex Vivo Costimulated Donor Leukocyte Infusion After Reduced-Intensity Conditioned Allogeneic Stem Cell Transplantation
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Experience with Axicabtagene Ciloleucel (Axi-cel) in Patients with Secondary CNS Involvement: Results from the US Lymphoma CAR T Consortium
Introduction: Axicabtagene Ciloleucel (axi-cel), a CD19 chimeric antigen receptor (CAR) T-cell therapy, was approved for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma in October, 2017. In the ZUMA-1 trial leading to axi-cel FDA approval, patients (pts) with prior or active secondary central nervous system (CNS) lymphoma involvement were excluded. A recent publication of 8 pts with secondary CNS lymphoma who underwent Tisagenlecleucel CAR T cell therapy was reported (Frigault M.J.2019). Since the two FDA approved CAR T cell products have a different neurotoxicity profile, understanding outcomes of axi-cel in this setting is important. We report here the real-world experience of 17 pts treated with axi-cel who had a history of secondary CNS involvement or had active CNS disease at time of CAR T infusion.
Methods: Seventeen academic centers from the US Lymphoma CAR T Consortium contributed data independently from the manufacturer. Data regarding secondary CNS involvement, management, and outcome were obtained in addition to CAR T therapy outcome for pts who were identified as having active, secondary CNS involvement at the time of evaluation for CAR-T therapy. Nine centers reported data on 17 cases with CNS involvement. Follow-up data was missing for one pt in the CNS cohort. Lee criteria or the modified Lee grading scale were used for cytokine release syndrome (CRS). CTCAEv4 or CARTOX grading were used for immune effector cells associated neurotoxicity syndrome (ICANS). All leukapheresed pts were included in the intention to treat (ITT) analysis for response rate and event-free survival (EFS). EFS was defined as date of leukapheresis until progression or death due to any cause. EFS was evaluated using Kaplan Meier curves with log-rank test. Differences in clinical characteristics and response between CNS and non-CNS pts were not formally tested due to small sample size and multiple comparison concerns.
Results: With a data cut-off of 4/30/2019, 300 pts underwent leukapheresis with intention to manufacture standard of care axi-cel. By the time of leukapheresis, 17 (6%) had secondary CNS involvement (4 parenchymal disease, 10 leptomeningeal/CSF, 3 data not available). Compared to the non-CNS cohort, baseline demographics were comparable (Panel A). Manufactured axi-cel was within specification for 100% of the CNS cohort. There was a higher rate of bridging therapy use in the CNS cohort 82% (1 steroids only, 2 radiation therapy, 12 systemic therapy) vs 52% in non-CNS cohort; p=0.022. Time from leukapheresis to CAR T infusion was 3.5 days longer in the CNS cohort as opposed to the non-CNS cohort: median time of 29.5 (range 20-76) vs. 26 days (range 5-67), (p=0.029), respectively. The CAR T infusion rate was 88% for the CNS cohort (15/17) compared to 93% (262/283) in the non-CNS cohort. Among the 15 infused pts in the CNS cohort, 10 had resolution of CNS involvement, and 5 had persistent active CNS disease at time of CAR T infusion.
After axi-cel infusion, the incidence of CRS and ICANS, of any grade or grade 3 or higher, were comparable between the CNS and non-CNS cohorts. Tocilizumab and steroid use were comparable between the two groups (Panel B). No seizures or cerebral edema were noted in the CNS cohort.
With a median follow-up of 10.1 months from leukapheresis (range 7.6-12.6), the ITT best overall response rates (CR+PR) and ongoing responses at month 6 between CNS and non-CNS cohorts were 75% vs. 59%, and 41% vs. 31%, respectively (Panel B). In the 5 pts with active CNS disease at time of CAR T infusion, the response of CNS disease were 2 CR, 1 PR and 2 PD as best response. In the 10 pts with resolved CNS disease at time of CAR T infusion, 2 PD were seen and both occurred systemically. EFS from leukapheresis was not statistically significantly different between CNS and non-CNS cohorts (6 months EFS: CNS cohort, 36%; non-CNS cohort 57%. HR=1.58, 95% CI: 0.83-3.01, p=0.16, Panel C). Six month EFS from the date of infusion for the CNS cohort was 49.9% (Panel D).
Conclusions: Pts attempting CAR T therapy with secondary CNS disease in the real world setting had similar rates of CAR T infusion, toxicity, and outcomes when compared to patients without CNS disease. Small sample size and limited follow-up caution the strength of conclusions for application to clinical practice, but these results support further investigation of CAR T in pts with history of or active secondary CNS lymphoma.
Figure
Disclosures
Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Nastoupil:Bayer: Honoraria; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Jain:Kite/Gilead: Consultancy. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cashen:Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Goy:COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Vu:Celgene: Other: Stock. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy. Munoz:Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend P
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Severity of Cytokine Release Syndrome Influences Outcome After Axicabtagene Ciloleucel for Large B cell Lymphoma: Results from the US Lymphoma CAR-T Consortium
•Durable responses to axi-cel are seen in patients who do not develop cytokine release syndrome .•In patients receiving axi-cel, grade 1 to 2 cytokine release syndrome is associated with best outcomes.•Patients with grade 3 to 5 experience the worst outcomes.
The majority of patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, develop cytokine release syndrome (CRS). Whether the lack of development of CRS with axi-cel is associated with inferior lymphoma outcomes is unknown. Additionally, relationship between CRS grade and lymphoma outcome is not well established.
The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. We analyzed the modified intent-to-treat population of 275 patients receiving axi-cel in two different ways: 1) Two group analysis comparing no CRS with any grade CRS; 2) Three group analysis comparing grade 0 CRS with grade 1 to 2 CRS, and grade 3-5 CRS.
In this large multi-center observational cohort of 275 patients receiving axi-cel, 9% (n = 24) did not develop CRS, 84% (n = 232) developed grade 1-2 CRS, and 7% (n = 19) developed grade 3 to 5 CRS. Patients without CRS, compared with those having any grade CRS, had similar overall response rates (ORR), lower complete response (CR) rates and inferior progression free survival (PFS) with no statistically significant difference in overall survival (OS). Patients experiencing grade 1 to 2 CRS had superior CR rate and PFS, as compared to those without CRS or with grade 3 to 5 CRS. Grade 3 to 5 CRS was associated with a worse OS.
Overall, durable responses were seen in patients that did not develop CRS, however grade 1 to 2 CRS was associated with better outcomes while those with grade 3 to 5 experienced the worse outcomes.
The majority of patients with large B-cell lymphoma treated with axicabtagene ciloleucel, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, develop cytokine release syndrome (CRS). Overall, durable responses were seen in patients that did not develop CRS, however grade 1to 2 CRS was associated with better outcomes while those with grade 3 to 5 experienced the worse outcomes
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Long-Term Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axicabtagene Ciloleucel: Results from the US Lymphoma CAR-T Cell Consortium
Abstract
Introduction:
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies.
Methods and Results:
The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion.
After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B); 1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status.
Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion.
Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19.
Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1)); other malignancies included squamous cell carcinoma of skin (n=3); sarcoma (n=1); endometrial (n=1); lung (n=1); mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy.
Conclusion:
This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk.
J.Y.S and M.D.J contributed equally; S.D and M.L contributed equally.
Figure 1 Figure 1.
Disclosures
Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy. Nastoupil: Pfizer: Honoraria, Research Funding; MorphoSys: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Bayer: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Lin: Gamida Cell: Consultancy; Juno: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Reagan: Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Curis: Consultancy. Oluwole: Curio Science: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. McGuirk: EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astelllas Pharma: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Goy: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; Xcenda: Consultancy; Acerta: Consultancy, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Phamacyclics: Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Genentech/Hoffman la Roche: Research Funding; MorphoSys: Honoraria, Other; Karyopharm: Research Funding; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Incyte: Honoraria; Medscape: Consultancy; Novartis: Consultancy, Honoraria; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Infinity/Verastem: Research Funding; Rosewell Park: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive Peer Exchange: Honoraria; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Hill: Pfizer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Andreadis: CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equit
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Bridging therapy with axicabtagene ciloleucel for large B-cell lymphoma: Results from the US lymphoma CAR-T consortium
During the manufacturing period of autologous chimeric antigen receptor (CAR) T cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of "bridging therapy" (BT) on the outcome of patients with relapsed/refractory large B cell lymphoma who received anti-lymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR T Consortium, with a median follow-up of 33 months (range: 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. The 52% (n=143) of patients who received BT had a higher baseline risk profile compared to patients who did not receive BT and these patients as a group had inferior outcomes than those who did not have BT. However, after propensity score matching between the two groups, there was no statistically significant differences in ORR (77% vs 87%, p=0.13), CR rate (58% vs 70%, p=0.1), PFS (HR=1.25, p=0.23), and OS (HR=1.39, p=0.09) between BT group and no BT group respectively. Analyzing effects of BT in the whole leukapheresed cohort regardless of receiving axi-cel (intention to treat analysis) showed similar results. Bridging radiation therapy resulted in outcomes similar to those observed with non-radiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival in patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage in using radiation-based BT over non-radiation-based BT
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Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium
MDJ and MTJ contributed equally; FLL and AG contributed equally.
Introduction
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are autologous anti-CD19 CAR T-cell therapies approved for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) who have failed at least two lines of systemic therapy. In the ZUMA-1 trial that led to axi-cel approval, the median time between apheresis and delivery of CAR T cells to the treating facility was 17 days (Neelapu, Locke et al. NEJM 2018). Bridging therapy, defined as lymphoma therapy given between apheresis and the start of lymphodepleting chemotherapy, was not permitted on ZUMA-1. By contrast, the pivotal JULIET trial for tisa-cel (Schuster et al. NEJM 2019) had a median time from enrollment to infusion of 54 days and 92% of patients received bridging therapy. Whether bridging therapy affects lymphoma CAR T outcomes is unknown. Here we evaluate patients receiving bridging therapy for axi-cel in a large multicenter cohort.
Methods and Results
The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data from lymphoma patients treated with standard of care (SOC) CAR T-cell therapy independently of manufacturers. As of 8/31/2018, 300 patients were apheresed with intent to manufacture SOC axi-cel for LBCL. Of the 23 patients that underwent apheresis for axi-cel and did not receive it, 20 had lymphoma progression or death that precluded CAR T infusion, of which 16 received bridging therapy. In this study, we analyze the modified intent-to-treat (mITT) population of 276 patients receiving CAR T infusion with a median follow up of 9 months. In this group, 146 (53%) patients received bridging therapy while 130 (47%) patients received no bridging therapy. Bridging therapy consisted of steroids alone (n = 35, 24%), chemotherapy (n = 73, 50%), radiation (n = 24, 16%), or targeted therapies (n = 14, 10%).
At baseline, a higher proportion of patients in the bridging therapy group had an ECOG score of 2 - 4 vs. 0 - 1 (bridging 24.8%, no bridging 6.1%, p <0.001), IPI score of 3 -5 vs. 0 - 2 (bridging 67.6%, no bridging 34.3%, p <0.001), bulky disease greater than 10 cm (28.2% vs. 13.0%, p = 0.002), immunohistochemical double expression of MYC and BCL2 (42.5% vs. 24.6%, p =0.004) and would not have met all the eligibility criteria for ZUMA-1 for reasons other than bridging therapy (48.6% vs. 30.0%, p = 0.002).
After axi-cel infusion, patients in the bridging group had similar rates of severe (grade 3 or higher) cytokine release syndrome (CRS) (8.2% vs. 5.3%, p = 0.34) and ICANS (35.2% vs. 28.2%, p = 0.25). However, the rate of ICU admission was higher in the bridging group (41.4% vs. 22.9%, p = 0.001) as was median length of hospital stay (15 vs. 14 days, p = 0.02). While data on cytopenias was not collected, use of G-CSF after CAR T therapy was higher in the bridging group (48.2% vs. 32.1%, p = 0.006).
In terms of outcomes, in multivariate analysis correcting for confounding features, there was no statistically significant difference in overall response rate (p = 0.2), complete response rate (p = 0.19), and progression free survival (p = 0.3) between bridging and no bridging groups; but bridging therapy was associated with significantly poorer overall survival (p = 0.001) and lymphoma specific survival (p = 0.019) (figure 1.). Both death due to lymphoma (33.1% vs. 13.0%) and death due to treatment-related mortality (TRM) (6.9% vs. 1.5%) were higher in the bridging group (p <0.001).
Conclusions
Lymphoma patients receiving bridging therapy had poorer prognostic factors at baseline and after axi-cel infusion experienced decreased lymphoma-specific and overall survival compared with patients with no bridging. This inferior outcome raises the possibility that bridging therapy may identify a sub-group of lymphoma patients with a different biology, or alternatively, bridging therapy may have an effect on the host or the tumor microenvironment that may impact CAR-T efficacy. With or without bridging, 7% of patients in our series did not receive axi-cel due to lymphoma progression and/or death. In addition, there may have been patients where bridging prevented progression or death prior to axi-cel infusion. Prospective evaluation of different bridging strategies is warranted to determine if any can improve outcomes after axi-cel, and/or if they should be utilized only for patients requiring emergent disease control during the manufacture period.
Disclosures
Jain: Kite/Gilead: Consultancy. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Lin:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBird Bio: Research Funding; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sorrento: Membership on an entity's Board of Directors or advisory committees. Lunning:Curis: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Bayer: Consultancy; DAVA: Consultancy; Gilead Sciences, Inc.: Consultancy; Kite: Consultancy; Novartis: Consultancy; OncLive: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Goy:University of Nebraska: Research Funding; Hakensackumc: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; Genentech: Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; TG therapeutics: Research Funding; Amgen: Research Funding. Munoz:Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of D
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Five Year Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axicabtagene Ciloleucel: Results from the US Lymphoma CAR-T Cell Consortium
Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 63.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 5-year OS and PFS (progression-free survival) estimates of 42.6% (95% CI, 32.8-51.9) and 31.8% (95% CI, 22.9-41.1), respectively (Neelapu, Blood 2023). We previously reported outcomes of axi-cel patients treated with standard of care therapy, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 58 months, as well as late outcomes of interest. Results The US Lymphoma CAR-T Consortium is comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel (n=298) as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After a median follow-up of 58 months, median OS was 34.9 months (95% CI 23.4 - 44.8) with the OS at 3, 4, and 5 years of 49.1% (95% CI 42.9 - 54.9%), 43% (95% CI 36.8 - 48.9%), and 40.3% (95% CI 34.2 - 46.4%), respectively. The median PFS was 8.7 months (95% CI 5.87 - 16.6) and the 3-,4-, and 5- year PFS were 36.1% (95% CI 30.4 - 41.8%), 30.7 (95% CI 25.2 - 36.4%), and 28.5% (95% CI 23 - 34.2%), respectively. Results of multi-variable modeling were similar to our prior analysis: male sex (HR 1.56, 95% CI 1.08 - 2.27, p =0.02); LDH above the upper limit of normal (HR 1.6, 95% CI 1.12 - 2.30, p = 0.01); ECOG status of 2-4 (HR 2.02, 95% CI 1.33 - 3.07, p = 1.5 (HR 5.68, 95% CI 2.21 - 14.6, p = <0.001) were associated with decreased OS. Factors associated with decreased PFS included male sex (HR 1.68, 95% CI 1.20 - 2.37, p = 0.003), LDH above the upper limit of normal (HR 1.82, 95% CI 1.31 - 2.53, p = <0.001), ECOG status of 2-4 (HR 1.93, 95% CI 1.30 - 2.86, p = 0.001), elevated bilirubin (HR 3.68, 95% CI 1.45 - 9.37, p = 0.006) and receipt of 3 or more prior lines of therapy (HR 1.49, 95% CI 1.03 - 2.13, p = 0.032). We also assessed events of interest including late PFS events and causes of non-relapse mortality (NRM). One hundred and ninety-one PFS events occurred after axi-cel infusion during the follow-up period, 151 due to lymphoma progression and 40 NRM. In the first 12 months post infusion, 131 progression events occurred,13 between 1 and 2 years post infusion, and 7 relapses after 2 years with the latest occurring 46.4 months after infusion. Thirteen NRM events occurred in the 1st year post infusion, 6 between 1- and 2-years post infusion and 21 occurring later than 2 years after infusion. Of the 40 NRM events, 21 were secondary to infection including fungal infections (n = 3, 2 candidemia, 1 candidemia and pneumocystis jiroveci pneumonia), JC encephalitis (n=1) and COVID-19 (n = 2). Nine deaths were attributed to secondary malignancy. Other causes of NRM included cerebral edema (n=1), HLH (n=1), intracranial hemorrhage (n=1), suicide (n=1), and unknown (n=6). The 5-year cumulative risk of relapse was 55.2% and the 5-year risk of non-relapse mortality was 16.2%. Excluding non-melanoma skin cancers, twenty-three of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=11), AML (n=2), CMML (n=1)); other malignancies included anal squamous cell carcinoma (ca) (n=1); histiocytic sarcoma (n=1); prostate ca (n=1); endometrial ca (n=1); lung ca (n=1); merkel cell ca (n = 1), mesothelioma (n=1), B-ALL (n = 1), and AITL (n=1). Conclusion This multi-center retrospective study showed similar 5-year results to the ZUMA-1 trial with a 5-year PFS and OS of 28.5% and 40.3%, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Non-relapse mortality was primarily due to infection and secondary malignancy. This report supports the curative potential of axi-cel but highlights the competing risk of NRM in this high-risk patient population
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Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience
Abstract
Introduction
Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved by the US FDA 10/18/2017, for the treatment of adults with relapsed or refractory (r/r) large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed lymphoma (tFL), and high-grade B-cell lymphoma (HGBCL) who have failed at least two prior systemic lines of therapy. In the pivotal ZUMA-1 trial, 108 patients (pts) with r/r DLBCL were treated with axi-cel: the best overall response rate (ORR) was 82% and complete response (CR) rate was 58%. At a median follow-up of 15.4 months, 42% of the pts had ongoing remission (Neelapu and Locke et al. NEJM 2017). Grade 3 or higher cytokine release syndrome (CRS) by Lee criteria and neurologic events (NEs) occurred in 13% and 31% of the pts, respectively. Here, we evaluated the real world outcomes of pts treated with standard of care axi-cel under the commercial FDA label.
Methods and Results
Seventeen US academic centers contributed data to this effort independently of the manufacturer. As of 6/30/2018, 211 pts were leukapheresed with intention to manufacture commercial axi-cel. Of these, 165 (78%) pts completed axi-cel infusion as of 6/30/18 and a further 23 (11%) pts are scheduled for axi-cel infusion in July 2018. Of the 23 remaining pts, 7 (3%) received axi-cel therapy on ZUMA-9 expanded access trial (NCT03153462) due to non-conforming cell therapy product, 15 (7%) pts died before axi-cel infusion (14 from lymphoma progression and 1 from sepsis) and 1 (1%) patient attained CR from bridging therapy and was not infused.
Safety was evaluable in 163 pts receiving axi-cel. Grade ³3 CRS and NEs occurred in 7% and 31% of pts. Tocilizumab was administered in 62% of pts and 57% received corticosteroids. Outside of lymphoma progression, 3 deaths occurred post-axi-cel; 1 due to HLH, 1 due to systemic candidiasis, and a third due to septic shock. There were no grade 5 NEs observed.
Response assessment was done for pts infused with axi-cel and who were re-staged at day 30 and/or day 100, or were deemed to have clinical progression. Of 112 pts evaluable at day 30, ORR was 79% with 50% CR, 29% PR, 6% SD and 14% with PD. Of 39 pts evaluable at day 100, 59% of pts had ongoing response (CR 49%, PR 10%).
At the time of abstract submission, more detailed patient characteristics and treatment course data were available in 134/165 pts infused. Median age was 59 (range 21-82) with 57% male. Performance status (PS) was ECOG 0-1 (81%), ECOG 2 (16%) and ECOG 3 (3%). By histology, 61% of pts had DLBCL including HGBCL, 31% had tFL and 8% PMBCL. Thirty-one percent had a prior autologous stem cell transplant. Bridging therapy between apheresis and infusion was given in 56% of patients, the majority of which consisted of chemotherapy. Sixty-six of 134 (49%) would not have met eligibility criteria for ZUMA-1 at the time of leukapheresis. Common criteria that would have made these patients ineligible for ZUMA-1 included ECOG PS >1 (n = 22), platelets <75k (n = 17), GFR <60 (n =12), active DVT/PE (n = 13), liver enzyme abnormalities (n = 10), a history of CNS lymphoma (n = 8), recent checkpoint inhibitor therapy (n = 7), ejection fraction <50% (n = 4), prior CD19 CAR T therapy (n = 4), and prior allogeneic transplant (n=2). Median time from leukapheresis to start of conditioning chemotherapy was 21 days and median time from leukapheresis to axi-cel infusion was 26 days. Median hospitalization period was 14 days.
Conclusions
This multicenter retrospective study delineates the real world outcomes of axi-cel CAR T-cell therapy for r/r aggressive B-cell lymphoma when used as a standard of care. Though limited by relatively short follow up, 30 day responses in the real world setting are comparable to the best responses observed on the pivotal ZUMA-1 clinical trial (Table 1). Importantly, safety appears comparable to the ZUMA-1 trial despite nearly half the pts failing to meet ZUMA-1 eligibility criteria. Updated results including PFS and OS will be presented at the meeting.
L.J.N. and M.D.J. contributed equally; D.B.M., S.S.N. and F.L.L. contributed equally.
Disclosures
Nastoupil: Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Janssen: Research Funding; Gilead: Honoraria; Juno: Honoraria; Novartis: Honoraria; Spectrum: Honoraria. Lunning:Celgene: Consultancy; Spectrum: Consultancy; Portola: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Juno: Consultancy; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Reagan:Seattle Genetics: Research Funding. McGuirk:Gamida Cell: Research Funding; Astellas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Pluristem Ltd: Research Funding. Deol:Novartis: Consultancy; Kite Pharmaceuticals: Consultancy. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Andreadis:Gilead: Consultancy; Genentech: Consultancy, Employment; Astellas: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Juno: Research Funding; Kite: Consultancy; Novartis: Consultancy, Research Funding. Munoz:Pfizer: Consultancy; Bayer: Consultancy, Speakers Bureau; Juno: Consultancy, Honoraria; Janssen: Consultancy; Genentech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Gilead: Speakers Bureau. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Vose:Kite Pharma: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria; Seattle Genetics, Inc.: Research Funding; Legend Pharmaceuticals: Honoraria; Merck Sharp & Dohme Corp.: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Bristol Myers Squibb: Research Funding; Incyte Corp.: Research Funding. Miklos:Genentech: Research Funding; Kite - Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding. Locke:Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor