Abstract: Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence. Significance: This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies—the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies. This article is highlighted in the In This Issue feature, p. 2221

Abstract: Background: Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionized the treatment of B-cell malignancies. However, a significant subset of these patients either fails to respond or eventually relapses. Moreover, in solid cancers, CAR T immunotherapy has had little to no success in the clinic so far. In recent years, several studies have shown the influence of commensal gut microbes on T cell function, in particular in the setting of checkpoint immunotherapy. Our group has recently demonstrated that modulation of the gut microbiota using antibiotics such as oral vancomycin (vanco) can enhance the efficacy of tumor-specific T cells in animal models. In this study, we sought to study the effect of vanco-induced dysbiosis on CART immunotherapy using murine models and clinical correlates. Methods and Results: We used the CD19+ A20 lymphoma and the B16 melanoma (transduced with CD19) murine models. Lymphoma- and melanoma-bearing mice were randomized to received oral vanco or vehicle alone (CTR), or in combination with either control untransduced murine T cells (UTD) or murine CART19 (4-1BB). Oral vanco or vehicle treatments started on the day of A20 cells injection and throughout the duration of the experiment (40-45 days). A20-bearing mice treated with CART19+vanco showed strikingly improved tumor control compared to either vanco alone or UTD+vanco (day 40 tumor volume in mm 3 (mean ± s.e.m): CTR=1,678.8±279.4, UTD=1,803.2±180, UTD+vanco=1,477±174, CART19=1,219±208, CART19+vanco=439.5±122.5 , CART versus CART+vanco Two Way Anova P & lt;0.0001). Of note, CART19+vanco also displayed a longer overall survival as compared to controls (UTD= 0/7 alive at day 45 (0%), UTD+vanco= 2/7 (28.6%), CART19= 4/8 (50%), CART+vanco= 8/8 (100%)). To evaluate whether gut microbiota modulation improves CART therapy against solid tumors, we engrafted mice with CD19+ B16 melanoma cells and treated them with murine CART19 or control T-cells with or without vanco. Mice receiving CART+vanco displayed increased tumor control as compared to CART alone (day 21 tumor volume in mm 3 mean ± s.e.m. CTR=1,820.7±131.3, UTD=1,315.9±360.8, UTD+vanco=1,223.6±297.3, CART=1,315±360.8, CART+vanco=443.8±131.9, Two Way Anova CART versus CART+vanco P & lt;0.0001). To investigate the mechanisms responsible for the improved anti-tumor activity, we analyzed gene-expression (nanoString) of 770 immune-oncology targets in tumor samples collected at day 5 after CART. The Ingenuity analysis showed up-regulation of the cross-presentation pathway in tumors of vanco+CART mice but not in CART alone. The functional validation of this mechanism was performed exploiting the physiological expression in A20 cells of the endogenous ecotropic murine leukemia provirus antigen gp70, also expressed in the colorectal cancer cell line CT26, which, however, lacks CD19 expression. Hence, purified T cells from CART19-treated A20-bearing mice were transferred into mice engrafted with CT26 tumors. These adoptively transferred T cells from CART+vanco group - but not the T cells obtained from mice treated with CART alone - displayed significant anti-tumor activity, (day 19 tumor volume in mm 3 (mean ± s.e.m): CTR= 1,360.6±123.3, CT26+CART= 932.9±234.9, CART+vanco= 402.5±139.4, Two Way Anova CART versus CART+vanco P & lt;0.0044). To validate these data, we generated patient-derived gut microbiota avatars, performing a "human to mouse FMT" and observed increased antigen presentation in avatars treated with CART19+vanco. Lastly, in a cohort of 30 B-cell acute lymphoblastic leukemia patients treated with CART19 (CTL019, NCT02030847), 4 patients exposed to oral vanco in the first 3 weeks after CART infusion showed higher CART19 peak expansion and higher peak cytokine levels (IL6, IL10, IL1Ra) in 3/4 patients exposed to oral vanco compared with matched unexposed patients. Conclusions: These results suggest that the modulation of the gut microbiota using vancomycin affects the outcome of CART therapy in preclinical models with better anti-tumor effect via cross-priming and enhanced CART expansion in tumor samples. In a retrospective cohort of patients with B-ALL receiving vancomycin after CART19 therapy, we observed higher CART expansion and serum inflammatory cytokines. Based on these observations, a clinical trial of oral vanco in patients receiving CD19-directed CAR T cells for B-cell lymphomas is planned. Disclosures Ruella: viTToria biotherapeutics: Research Funding; Tmunity: Patents & Royalties; Novartis: Patents & Royalties; BMS, BAYER, GSK: Consultancy; AbClon: Consultancy, Research Funding. Frey: Novartis: Research Funding; Sana Biotechnology: Consultancy; Kite Pharma: Consultancy; Syndax Pharmaceuticals: Consultancy. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current Employment, Current equity holder in publicly-traded company; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Unity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Schuster: TG Theraputics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding.

Abstract: Introduction: Cellular immunotherapy with CD19-targeted chimeric antigen receptor (CAR) T cells has provided new therapeutic options for patients with high-risk hematologic malignancies. Following this therapy, patients may experience disease relapse or CAR-mediated toxicity due to cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Recent studies have confirmed that the intestinal microbiome can modulate the anti-tumor immune response to chemotherapy, immune checkpoint blockade, graft-versus-host disease after allogeneic hematopoietic cell transplantation, and adoptive cellular therapy. The contribution of the intestinal microbiome on the function of CAR T cells in vivo both with respect to their anti-tumor function and their propensity to induce toxicities is not known. Hence, in a multi-center study we analyzed the association between clinical outcomes and (1) antibiotic exposure prior to CAR T cell infusion and (2) the composition and diversity of the fecal microbiome. Methods and Results: We retrospectively collected clinical data and antibiotic exposures from patients with acute lymphoblastic leukemia (ALL, n=91) and non-Hodgkin lymphoma (NHL, n=137) treated with investigational or commercial CD19 CAR T cells at Memorial Sloan Kettering Cancer Center (MSK) and the University of Pennsylvania (Penn). We considered any antibiotic exposure between day -30 and the day of CAR T cell infusion. We focused our analysis on anaerobe-targeting antibiotics used in the setting of neutropenic fever: piperacillin-tazobactam, imipenem-cilastatin, and meropenem (here referred to as "P-I-M"). We found that forty-seven (20.6%) of 228 patients were exposed to P-I-M in the four weeks before CAR T cell infusion. Patient characteristics at the time of CAR T cell infusion were similar between the P-I-M-exposed and not-exposed groups, although a worse performance status was observed in patients with NHL treated with P-I-M. We found that overall survival (OS) was significantly decreased following CAR T cell infusion in patients exposed to P-I-M (Fig 1A; OS HR, 2.58; 95% CI, 1.68 - 3.98; p= & lt;0.001). A subgroup analysis of the patients with NHL also demonstrated decreased OS associated with P-I-M exposure whether the costimulatory domain was CD28 or 4-1BB (data not shown). Next, we queried whether patients exposed to P-I-M had more aggressive disease. We evaluated potential confounders for the findings in uni- and multi-variable models. Importantly, exposure to P-I-M remained a strong predictor of decreased OS (HR, 2.58; 95% CI, 1.55 - 4.3; p= & lt;0.001) (Table 1). Exposure to P-I-M was also associated with increased ICANS (p= 0.023) but not CRS (p= 0.058) in patients in the combined NHL and ALL cohort as well as in patients with NHL (CRS: p= 0.154, ICANS: p= 0.002) (data not shown). We also prospectively collected baseline fecal samples prior to cell infusion from CD19 CAR T cells recipients (n=48) at MSK and Penn. Samples were submitted for 16S RNA sequencing of the V4-V5 region on the Illumina MiSeq platform and the amplicon sequence variants (ASVs) were annotated according to the NCBI 16S database using BLAST. In comparison to healthy controls (n=30), we found that alpha-diversity was significantly lower in fecal samples from CAR T cell patients (p= 0.0023, Fig 1B) and the composition of fecal samples was significantly different (p= & lt;0.001, Fig 1C). Finally, linear discriminant analysis effect size (LEfSe) identified an increased abundance of Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae in patients who achieved a Day 100 complete response (CR) and those who experienced CAR-mediated toxicity (data not shown). Conclusion: Our results suggest that exposure to antibiotics, in particular P-I-M, in the four weeks before therapy was associated with worse survival. Profiling of the baseline fecal microbiome samples by 16S revealed that CD19 CAR T cell patients presented with evidence of an altered fecal microbiome as measured by lower alpha-diversity and a composition that is distinct from that of healthy controls. Finally, we identified bacterial taxa that were associated with Day 100 CR and CAR-mediated toxicity. Our findings indicate that the intestinal microbiome can affect the efficacy of CD19 CAR T cell therapy and provides a rationale to target the intestinal microbiome to improve clinical outcomes of patients treated with cellular therapies. Figure 1 Figure 1. Disclosures Smith: Janssen: Consultancy, Honoraria. Gomes: Xbiome: Current Employment. Schluter: Postbiotics Plus LLC: Other: cofounder. Park: Kura Oncology: Consultancy; BMS: Consultancy; Servier: Consultancy; Autolus: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Jain: Targeted Healthcare Communications: Consultancy; Bristol Myers Squibb: Other: for advisory board participation; CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding. Pennisi: Gilead Sciences: Consultancy. Perales: Miltenyi Biotec: Honoraria, Other; Novartis: Honoraria, Other; Omeros: Honoraria; NexImmune: Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Nektar Therapeutics: Honoraria, Other; Cidara: Honoraria; Servier: Honoraria; Sellas Life Sciences: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other. Garfall: Amgen: Honoraria; CRISPR Therapeutics: Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Tmunity: Research Funding. Landsburg: Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Takeda: Research Funding. Gerson: Kite: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy. Svoboda: Imbrium: Consultancy; Genmab: Consultancy; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Rivière: FloDesign Sonics: Other: Provision of Services; Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); Juno Therapeutics: Patents & Royalties. Porter: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons Publishing: Honoraria; Tmunity: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Sadelain: NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Atara Biotherapeutics: Patents & Royalties; Ceramedix: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Juno Therapeutics: Patents & Royalties; Minerva Biotechnologies: Patents & Royalties. Frey: Novartis: Research Funding; Kite Pharma: Consultancy; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties; Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company. Pamer: Diversigen: Other: Advisory board; Bristol Myers Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis and Ferring Pharmaceuticals: Honoraria. Peled: DaVolterra: Consultancy; MaaT Pharma: Consultancy; CSL Behring: Consultancy; Seres Therapeutics: Research Funding. Ruella: BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; AbClon: Consultancy, Research Funding; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. van den Brink: WindMILTherapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Priothera: Research Funding; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Amgen: Honoraria; Frazier Healthcare Partners: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Rheos: Honoraria; Therakos: Honoraria; Jazz Pharmaceuticals: Honoraria; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Pharmacyclics: Other; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards .

Abstract: Background: High-dose chemotherapy followed by autologous stem cell transplantation (SCT) is the current standard of care for myeloma patients for attaining deeper responses. Generic melphalan formulations that were used for more than half a century were susceptible to several challenges (marginal solubility, limited chemical stability after reconstitution and prone for hydrolysis, requirement of propylene glycol as a co-solvent, etc). Evomela™, a Captisol®-stabilized propylene glycol-free melphalan preparation recently obtained FDA indication for use as a high-dose conditioning treatment prior to SCT in patients with myeloma. However, no comparative data relative to conventional melphalan exists. The objective of our study was to evaluate if Evomela™, a more stable compound, can potentially be delivered at the intended dose and deliver higher response rates relative to melphalan. We also reviewed the safety of Evomela™ compared to the generic formulation in this retrospective analysis. Methods: This is a retrospective analysis comparing 2 sequential cohorts of myeloma patients that underwent autotransplant at a single institution. Our institution switched to Evomela™ on September 15th 2016. Approximately 201 patients received a single autotransplant with Evomela™ from September 15th 2016 until September 14th 2017. The control group (193 patients) received conventional melphalan from September 15th 2015 until September 14th 2016. Both Evomela™ and the conventional melphalan were administered on the same day of transplant with the same amount of infusion time. Patient characteristics, toxicity and responses at day 100 were collected and compared between the 2 groups. Fischer's exact and Cochran-Mantel-Haenszel tests were used to compare responses and toxicities. Results: Median age of the patients is 62 years (range 16-78). Patient and transplant characteristics were summarized in Table 1. Both of the groups are balanced, except for 2 variables. The Evomela™ group had higher rates of patients with CAD and 8% more patients received RVD induction therapy. All of the pre-transplant parameters, conditioning regimens and median CD34+ cells infused were similar. The post-SCT ≥VGPR rate was significantly higher for Evomela™ relative to melphalan (85.3% vs 78%, p=0.043), especially when the ≥VGPR rates prior to SCT were similar across the 2 groups (58.5% vs 56.5%, p=0.381), Fig 1. While the difference is seen for both 200 mg/m2 (63.8% vs 54.8%) as well as 140 mg/m2 (91.9% vs 80.4%), the ∆ change (pre-SCT VGPR to post-SCT VGPR) is highly significant among patients receiving Evomela™ 140 mg/m2 vs melphalan (37.5% to 91.9% for ∆ 54.4% vs 61.7% to 80.4% for ∆ 18.7%, p 〈 0.001). Higher rates of neutropenic fevers were seen in the Evomela™ group (p=0.032) but the safety profile, day 30 transplant related mortality, readmission rates, ICU transfers and cardiac complications were similar to melphalan, as outlined in Table 2. Conclusions: These results suggest that by using Evomela™ the intended dose of the alkylating agent is delivered when compared to the conventional melphalan formula. Considering the similar complication rates and safety profile while obtaining higher and deeper response rates supports the use of Evomela™. Disclosures Kaufman: BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: 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; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Waller:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Kalytera: Consultancy; Cambium Medical Technologies: Consultancy, Equity Ownership; Celldex: Research Funding. Heffner:Kite Pharma: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.