ALBERT

Description: A mechanistic understanding of river avulsion location and frequency is needed to predict the growth of alluvial fans and deltas. The Huanghe, China, provides a rare opportunity to test emerging theories because its high sediment load produces regular avulsions at two distinct nodes. Where the river debouches from the Loess plateau, avulsions occur at an abrupt decrease in bed slope and reoccur at a time interval (607 yrs) consistent with a channel-filling timescale set by the superelevation height of the levees. Downstream, natural deltaic avulsions reoccur at a timescale that is fast (7 yrs) compared to channel-filling timescale due to large stage-height variability during floods. Unlike the upstream node, deltaic avulsions cluster at a location influenced by backwater hydrodynamics and show evidence for episodic downstream migration in concert with progradation of the shoreline, providing new expectations for the interplay between avulsion location, frequency, shoreline rugosity and delta morphology.

Description: Background Multiple myeloma (MM) remains incurable despite treatment advances. While passive immunotherapy such as anti-CD38 antibodies is highly effective, active immunotherapy may provide long-lasting remissions by virtue of triggering memory. A phase 1 nivolumab study, an antibody targeting programmed death-1 (PD1), was unable to yield any responses in multiply relapsed MM patients. Conversely, preliminary trial data of lenalidomide combined with pembrolizumab, a different anti-PD1 antibody, found significantly higher response rates. These two differing outcomes reflect our limited understanding of checkpoint inhibition and immunotherapy in MM. There is a paucity of preclinical models to guide therapeutic studies. Cell lines and xenografted murine models are incapable of exploring active immunotherapy due to a lack of microenvironment and endogenous immune cell signals. Furthermore, malignant cells responsive to drugs in 2-dimensional (2D) cultures are known to display a more resistance in 3D. We have previously demonstrated that B-cell malignancies can be accurately studied using a 3D culture system of patient bone marrow mononuclear cells (BMCs) and can better inform translational trials. Herein we describe an ex vivo, 3D tissue culture model of patient-derived MM samples to more accurately test therapeutics including checkpoint inhibition using ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA) which is crucial in co-stimulatory signaling of effector T-cells. Methods A 3D extracellular matrix was created using matrigel in 12-well plates. BMCs were isolated from marrow aspirates of 5 MM patients at time of diagnosis and individually cultured. Each patient sample was tested for sensitivity against increasing concentrations of ipilimumab (1X, 3X, and 10X clinical doses) added into supportive medium. Plates were monitored visually by microscopy followed by harvest on day 21 using enzymatic degradation. Unique clonotypic heavy chain immunoglobulin rearrangement (IgH VDJ) from each sample was sequenced, validated and used for semi-quantitative PCR. Semi-QT PCR with clone-specific primers estimated malignant cell survival after harvest. Flow cytometry was used to define cell populations present in culture and to correlate with clonotypic PCR data. T-cell mediated activity was examined by reverse transcription of trizol-extracted, T-cell RNA after harvest. Results All samples were successfully cultured, followed for 21 days and harvested. Flow cytometry confirmed presence of T-cell subsets, B-cells, NK cells and dendritic cells before and after culture in 3D. Minimal depletion of clonotypic cells was observed at 3x clinical levels of drug. At 10x simulated clinical therapeutic levels, 3 MM samples demonstrated 〉90% death of clonotypic MM cells while the other 2 demonstrated 62% and 72% death, respectively, compared to untreated control cultures. The extent to which the drug diffuses into the matrigel is as yet unknown. Flow cytometry of harvested cells suggest that T-cells demonstrate a modest shift toward CD4 and CD8 effector cells. Preliminary mechanistic data from one MM sample using trizol-extracted RNA and reverse transcriptase PCR harvested at 21 days from 3D culture suggests that anti-malignant, cytotoxic T-cell effect may be driven by granzyme B expression. Expanded data from the remaining samples will be presented. Conclusions We demonstrate that an ex vivo 3D tissue culture model of MM is both feasible and informative in studying immunotherapy. By culturing unselected BMCs which include stromal cells, immune cells and malignant populations, the 3D culture more closely mimics the tumor microenvironment with both the patient's immune system present as well as stromal supportive signals. In this study, we show that in the presence of active immune effector cells, ipilimumab has activity against patient-derived MM cells. The data suggests the importance of targeted cytotoxic T-cell activation as a primary mechanism of action. We have previously studied standard MM therapeutics such as cytotoxic chemotherapy, immunomodulatory drugs, and proteasome inhibitors in the same way. Consequently, this model is well positioned to study other immunotherapies such as other checkpoint inhibitors, cellular therapy, and combinations. Further testing with therapeutics targeting PD1/PDL1, and adenosine receptors are underway. Disclosures Venner: Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Belch:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

Description: BACKGROUND Outcomes in multiple myeloma have improved dramatically over the last decade however, optimal sequencing of therapy remains unknown. Specifically, in an era where post-transplant lenalidomide (L) maintenance is now as established standard of care, questions remain around the utility of full dose L-based regimens in second line therapy. In this series, we sought to evaluate the impact of different regimens used at first relapse in patients who received autologous stem cell transplant (ASCT) in the frontline setting treated with and without lenalidomide maintenance (LM). We focused on the impact of L-based therapies in patients relapsing on LM. METHODS Using our prospectively maintained institutional MM database we retrospectively analyzed patients treated at the Cross Cancer Institute from January, 2005 to January, 2016 to ensure 2 years of follow-up for surviving patients. 4 categories were identified based on 2 variables: receipt of LM following 1st line therapy (yes or no) and receipt of L-based 2nd line therapy (yes or no). The primary endpoint was 2nd PFS defined as time of initiation of second line therapy to relapse, death or last follow-up. OS was defined as time of initiation of first line induction therapy to death or last follow-up. Second OS was defined as time of initiation of second line therapy to death or last follow-up. Survival statistics were determined using the Kaplan-Meier method with SPSS software. A p - value of

Description: Introduction Non-Hodgkin lymphoma impacts a patient's physiology beyond manifesting as lymphadenopathy, which was recognized in the original Ann Arbor staging such as B-symptoms. Likewise, cancer cachexia is prevalent across tumor types, but it is felt to be a late feature of advanced disease. We have previously demonstrated that cancer patients may have muscle changes well before cachexia's onset such as a reduced muscle radiation attenuation as seen on computed tomography (CT) imaging. This drop in skeletal muscle radiographic density (SMD) was shown to be prognostic and possibly predictive of rituximab-containing treatment response in retrospective studies of follicular and diffuse large B-cell lymphomas1. This post hoc analysis of LYM 3002 (NCT00722137), a phase III randomized trial of newly diagnosed mantle cell lymphoma (MCL) patients, sought to investigate SMD's impact in both MCL and validate it in prospectively collected data. Methods 487 newly diagnosed MCL patients were randomized 1:1 between R-CHOP or VR-CAP (vincristine or bortezomib at 1.3 mg/m2 d1, 4, 8, 11 q3wk) for a total of 6-8 cycles in LYM 30022. CT images at pre-treatment, 12-weeks post treatment, and 26-weeks post treatment were anonymized (for blinding) and reviewed to measure patient SMD at the L3 vertebral body level. Based on prior retrospective data, normal SMD was defined as ≥ 41 and 33 Hounsfield Units for non-overweight (BMI 〈 25 kg/m2) and overweight (BMI ≥ 25 kg/m2) patients, respectively. Patients with normal vs. low SMD were compared for differences in investigator-assessed progression free (PFS) and overall survival (OS). Cox proportional hazards multivariate analysis weighed SMD's significance against other known prognostic factors: gender, MIPIb score (accounting for Ki-67 score), and treatment received. Results Of 487 patients, 478 had CT images available for review and were split equally between either treatment arm. 42.5% (n=203) were found to have low SMD at baseline. At a median follow-up of 40 months, patients with low vs. normal baseline SMD had substantially poorer, investigator-assessed, median PFS (16.3 vs. 23.7 months, hazard ratio [HR] 1.52, p

Description: BACKGROUND: Non-Hodgkin B cell lymphomas are often infiltrated by immune effector cells including T, NK and dendritic cells. But despite their presence within the tumor they fail to control tumor growth. Some T cells can even play a supportive role to maintain the tumor and prevent the function of anti-tumor immune cells. Regulatory T cells (TRegs) function normally to dampen immune responses and prevent auto-immunity by direct cell contact or by secreting suppressive cytokines i.e. TGF-b and Interleukin-10. Follicular Lymphoma tumor cells can induce the conversion of CD4 T cells into TRegs (1-3), thereby evading anti-tumor immune responses. Follicular helper T cells (Tfh), another class of regulatory T cells, are found within normal follicles of lymphoid organs. Migrating into the germinal center, they promote the survival and differentiation of follicular B cells. In lymphoma, Tfh cells can send a survival signal to tumor B cells through CD40L/CD40 interactions (4). STUDY: In an ongoing multi-center phase I clinical trial (NCT02266147), patients with previously untreated low-grade lymphoma receive low dose (2Gyx2) radiotherapy to a single, tumor site, followed by intratumoral injection into the same site of a CpG-ODN (SD-101, Dynavax Technologies), an immune-modulatory molecule that targets Toll-like Receptor 9 (TLR-9). Doses ranged from 1mg to 8mg per injection in successive cohorts. A fine needle aspirate (FNA) of the treated site is performed before, one week after the first injection, and 1 week after the 5th and final weekly injection of CpG-ODN. FNA samples are sent to a central site by overnight delivery in media with 5% fetal calf serum. They are processed within 24 hours and stained for flow cytometry with panels of antibodies to delineate T, B, NK, dendritic, myeloid cells, and their subsets. Antibodies against activation antigens, as well as T cell exhaustion, inhibition and function are also used to characterize these cells. To date, 12 patients have been entered into the dose escalation phase of this study: 10 follicular lymphoma, 1 chronic lymphocytic lymphoma and 1 small lymphocytic lymphoma. Nine of 12 patients had FNAs that yielded enough viable cells for evaluation pre and 1 week post treatment. RESULTS: Therapy has been well tolerated. Local injection site reactions and fever, the most common side effects, resolved by 48 hours. There have been no related SAEs. The treated site regressed in all patients per CT scan at 3 months post treatment. The early evaluation of untreated lesions documented 1 PR. The remaining patients have stable disease with all but one having systemic tumor regressions ranging from 14% to 28%. Seven out of 9 patients evaluable by flow cytometry had an increase in total T cells at the treated site 1 week following the first dose of CpG ranging from 18 to 〉 300% above baseline in both the CD4 and CD8 compartments. More interestingly, there was a reduction of TRegs as a percentage of total T cells in 7 of 9 patients (average reduction: 21.3 ± 10.6%). A single patient with an increase in untreated tumor burden of 15% showed no reduction in TRegs. There was also a reduction of Tfh cells in 8 of the 9 evaluable patients (average reduction: 87.2 ±7.2%). One patient with SLL had no Tfh cells pretreatment. Figure 1A and B shows a representative example of TReg and Tfh cell depletion within the same FL patient. CONCLUSION: Immune modulating therapies can be delivered directly into a tumor to minimize systemic toxicity and induce changes in the tumor microenvironment while potentially inducing a global anti-tumor immune response. In this case, the combination of intratumoral CpG and low-dose radiation reduced the proportion of TRegs and Tfh cells, thereby modulating their immune inhibitory effects and tumor growth promoting effects, respectively. This clinical trial is ongoing and open to accrual. Monitoring the cell populations in the tumor site by repetitive sampling and analysis by flow cytometry reveals the pharmocodynamic effects of anti-cancer therapies, especially those intended to trigger anti-tumor immune responses. This knowledge can be used to tailor therapies and to influence the choice and scheduling of combinations of agents designed to target specific cell populations. 1. Yang Z-Z, et al. Blood. 2007;110:537-44. 2. Ai WZ, et al. Int J Cancer. 2009 Jan 1;124(1):239-44. 3. Mittal S, et al. Blood. 2008;111:5359-70. 4. AmŽ-Thomas P, et al. Blood. 2015 Apr 9;125(15):2381-5 Figure 1. Figure 1. Disclosures Bartlett: Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending. Coffman:Dynavax Technologies: Employment. Janssen:Dynavax Technologies: Employment. Levy:Bullet Biotechnology, Inc.: Consultancy.

Description: Introduction MCL has a poor prognosis. In eligible patients, intensifying frontline, CHOP-like regimens (e.g., cytarabine) as well as high-dose chemotherapy and autologous stem cell transplant (HDT/ASCT) consolidation in first remission have improved progression free survival (PFS) but less so, overall (OS). Preclinical animal models show benefits of adding tumor-specific T-cells to ASCT. CpG (PF-3512676) is a toll-like receptor 9 (TLR9) agonist and an effective vaccine adjuvant that induces costimulatory molecule expression on both antigen-presenting and MCL cells. This phase I/II clinical trial (NCT00490529) adds autologous T-cell transfer, harvested from patients after vaccination with CpG-activated autologous MCL cells - a maneuver termed immunotransplant. This is a planned interim analysis for safety and efficacy triggered by the first 20 patients reaching 1 year post ASCT. Methods Prior to therapy, subjects' tumor cells are collected by biopsy or apheresis and patient-specific vaccine is created by incubating fresh tumor cells with CpG (3 mcg/mL PF-3512676, 72-hr culture), then irradiated and cryopreserved. Patients receive induction chemoimmunotherapy of physician's choice. Patients achieving at least partial response (PR) then receive 3 subcutaneous autologous tumor vaccinations (1 x 108 cells/dose) mixed with CpG (18 mg) every 4-7 days. Primed T-cells (≥ 1 x 1010 CD3 cells) were collected by apheresis 2-4 weeks following vaccine 3 and a rituximab (375 mg/m2) B-cell purge. After standard HDT/ASCT (conditioning = BCNU, cyclophosphamide, etoposide), primed T-cells and a 4th vaccination are given on day+1. A 5th CpG-MCL vaccination followed 3 months post ASCT. The primary endpoint of this study is freedom from minimal residual disease (MRD) at 1 year post ASCT, measured by presence of patient-specific, malignant B-cell VDJ sequence in peripheral blood (ClonoSeq™, analyzed at a sensitivity of ≥ 1 clone/10,000 leukocytes) -an endpoint previously shown to be highly prognostic. Secondary endpoints include PFS, OS, and immune response to vaccine. 59, transplant-eligible, MCL patients are targeted for accrual in this 2-stage design. Results In this interim analysis of 24 patients accrued, 20 have surpassed 1 year post ASCT. All patients had Stage IV disease. Median values included (range): follow-up 43.5 months (11.5-60.1), age 60 years (47-70), and MIPI score 5.9 (5.1-7.8). Vaccine was made from biopsy alone (n=12), apheresis alone (n=9), or both (n=1). Frontline therapy included R-CHOP (n=7), R-hyperCVAD (n=14), alternating R-CHOP/R-DHAP (n=2), and R-EPOCH (n=1). 19 patients achieved complete response while another 3 had PR. All responding patients were vaccinated, able to yield sufficient T-cells for adoptive transfer, and proceeded through standard HDT/ASCT. At 1-year post ASCT, freedom from MRD was 90.5% (n=21). 2 patients did not reach 1-year post ASCT. One died from an ASCT complication (metapneumovirus) while the other relapsed 6 months following ASCT (included in MRD analysis). The most common toxicity due to CpG-MCL vaccine was erythematous rash at injection site (90.9%, n=20, each grade 1). No serious adverse events were seen related to vaccines or adoptive T-cell transfer. All patients had successful hematopoietic recovery, but two were delayed and received backup stem cell infusions with eventual recovery. Though median PFS and OS have not been reached, 3-year PFS and OS at interim analysis are 54.5% and 63.6%, respectively (intention to treat). In this data set, higher expression of co-stimulatory molecules (such as CD40, CD80, and CD86) on a subject's MCL in response to CpG was associated with freedom from MRD (p =0.02). Post-ASCT, higher peripheral T-cell granzyme and perforin response to ex vivo re-challenge with autologous MCL cells was also associated with freedom from MRD (p =0.01). Conclusions The addition of CpG-activated, whole MCL vaccination and autologous, adoptive T-cell transfer to standard therapy appears both feasible and safe. At interim analysis, the 1-year freedom from MRD surpasses rates previously reported in other studies and warrants further investigation. To date, 46 patients have either completed and/or are continuing to undergo study treatment and the study remains open to accrual for patients newly diagnosed with MCL. Disclosures Miklos: Pharmacyclics: Research Funding. Rezvani:Pharmacyclics: Research Funding. Faham:Adaptive Biotechnologies: Employment. Levy:Immune Design: Research Funding; Dynavax: Research Funding.

Description: Background: Receptor for hyaluronan-mediated motility (RHAMM) or CD168 has been a promising target for MM immunotherapy because it is overexpressed in MM cells. RHAMM has been tested as a target for an anti-RHAMM peptide vaccination approach in MM and other hematological malignancies. Although RHAMM peptide-induced immune response in patients, clinical outcomes were mixed, that can be a result of equal expression levels of RHAMM in different subpopulation of bone marrow (BM) cells in MM patients and healthy donors (HD). To enhance current RHAMM-peptide and future immunotherapeutic approaches, we investigated the cause of altered RHAMM mRNA splicing in MM patients. mRNA splicing has the potential to produce numerous mis-spliced genes, creating novel disease markers; some resulting proteins are likely to contain neoantigens selectively expressed on MM tumor cells. Methods/results: Splicing alterations can be caused by single nucleotide variations (SNVs) that affect splicing regulatory elements (SREs), or by deregulated splicing factors (SFs). We evaluated the incidence of SNVs located in the vicinity of the RHAMM. We identified a total of 57 SNVs: 72% SNVs are in the intronic region, and 28% are in the RHAMM coding region. We used the "HEXplorer" tool and predicted that four SNVs have the potential to contribute to aberrant RHAMM splicing in MM either by altering SF binding to SREs or by impacting splice site selection. Predicted SNVs were evaluated using an in vivo splicing assay to identify SNV-clusters causing aberrant RHAMM splicing. We have observed progressive overexpression of core SF PTBP1/2 (polypyrimidine track-binding protein) in MM patients and associated with disease progression. Since SNVs on the RHAMM modulate canonical SF binding sites, we tested the effects of PTBP1/2 deregulation on RHAMM splicing. We expressed PTBP1/2 in H929 cells, and then evaluated the RHAMM splicing pattern in transfected cells at a single cell (SC) level. SC analyses showed that overexpression of PTBP1/2 increased (2.5-fold) the RHAMM-V3:FL ratio in MM cells. SC analyses also identified overexpression of the RHAMM-V3 splice variant in 18% of H929 SCs expressing PTBP1, and in 37% of cells expressing PTBP2, confirmed at the single cell (SC) level. In BM-infiltrating myeloid cells, analyses showed 50% of myeloid cells express the RHAMM-V3 variant alone, and 79% of plasma cells (PCs) express this variant in combination with RHAMM-FL. Moreover, the RHAMM-V3/FL ratio in PCs is elevated (2.6-fold), further confirming a correlation between the RHAMM variant ratio and the clinical outcome. Next, we determined RHAMM-V3/FL ratios in BM stromal cells from 16 MM patients: MM-BMSC samples exclusively express the RHAMM-V3 in combination with RHAMM-FL and the RHAMM-V3:FL is 1.8 fold. In BMSC samples derived from healthy donors (HD), we detected relatively low-level expression of RHAMM-FL as compared to expression levels of RHAMM-FL in MM patients, while RHAMM-V3 transcripts were undetectable. SC analysis of RHAMM FL and splice variant transcripts in MM BMSC and HD-BMSC agreed with the analyses done on the MM HD-BMSC bulk population. We did not detect any MM BMSC cells expressing RHAMM-V3 alone and the RHAMM V3/FL ratio was 1.6-fold, which is lower than that in MM-PCs. MM-BMSC screening also identified a new splice variant of RHAMM, that was absent in MM PCs or in MM myeloid cells. Conclusions: Our study suggests that aberrant RHAMM splicing in MM can result from SNPs/SNVs affecting SRE due to the upregulation of PTBP1/2. Our study is the first to show that the RHAMM-V3 variant is associated with PTBP2 overexpression. The identification of cell type-specific RHAMM splicing events identifies novel targets for improved immunotherapy in MM. Disclosures Chu: Celgene: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria; Teva: Consultancy; Amgen Inc.: Honoraria. Anderson:C4 Therapeutics: Other: Scientific founder ; OncoPep: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board.

Description: Background: Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies including multiple myeloma (MM), but minimal residual disease and drug resistance underlie relapses in MM. Although many genetic and epigenetic alterations regulate MM progression, MM cells are not autonomous. Dynamic interactions between MM cells and cells of the bone marrow (BM) microenvironment have been reported by our group and others. MM plasma cells (PCs) depend on interactions with bone marrow stromal cells (BMSCs) for their survival and growth, but little is known about the specific genetic events taking place in the MM BM microenvironment. Methods: Here we report a detailed analysis of the genetic and epigenetic events that are characteristic of MM BMSC as compared to HD-BMSC interacting with BM PCs. To evaluate genetic and epigenetic landscapes, RNA was extracted from bulk sorted populations of 16 MM-BMSC, 3 HD-BMSC, and 10 autologous MM cells. We prepared libraries for 32 samples using the NEBNext Ultra II Stranded Poly A kit, and then sequenced on the NextSeq 500, PE150. Sequencing data were analyzed using a custom computational and statistical pipeline at the Department of Biostatistics, School of Public Health and Partek software. Results: Unsupervised clustering showed that MM-BMSC samples clustered as a distinct and completely separate cluster from HD-BMSC and autologous MM cells. Gene level analyses of these three groups identified 990 genes differentially expressed (upregulated or downregulated, P〈 0.005). Sequential filtration analyses of the differentially expressed genes in MM-BMSC identified significant deregulation of : transcripts in the Jak-STAT signaling pathway (JAK3, PIM1, IL6, CSF2R, AKT1/2, BCL2L1, CDKN1A and range of IL transcripts); genes encoding extracellular matrix interacting proteins (CD36, CD49, LAMA3, CD44, CD47); and various plasma membrane proteins that define different subpopulations of hematopoietic cells. These genes were deregulated in 〉24% of MM-BMSC samples analyzed as compared to HD-BMSC samples. These transcripts were downregulated in autologous tumor cells. Next, we interrogated the epigenomic landscape and identified the splicing signature of MM-BMSC as compared to HD-BMSC, and autologous MM cells. Comparison of the splicing patterns (exon skipping, intron retention, novel splice acceptor and/or donor activation) of these three distinct groups showed that a total of 2,100 genes were differentially expressed and 566 were alternatively spliced among the three groups (P 〈 0.01). These analyses identified a limited number of the transcripts with ~3% significantly spliced in MM-BMSC compared to HD-BMSC. However, comparing MM-BMSC splicing events to MM cells splicing events, we identified 〉30% of genes which were alternatively spliced in MM cells but not in MM-BMSC. Further, gene enrichment and pathway analyses identified a selective set of transcripts that were alternatively and differentially spliced in MM-BMSC including genes involved in MAPK and Ras signaling pathways, homologous recombination, mismatch repair, and adherens junction. Conclusions: Taken together, our studies identified marked differences between important stromal elements in MM- and HD-BM. We identified genes that were specifically upregulated/suppressed in MM-BMSC compared to MM-cells and HD-BMSC. Within MM BMSCs, we identified several splicing events on genes of signaling pathways implicated in development and progression of MM. Furthermore, altered splicing events identified on these transcripts represent potential new immunotherapeutic targets. Disclosures Chu: Gilead: Honoraria; Celgene: Honoraria; Teva: Consultancy; Amgen Inc.: Honoraria; AstraZeneca: Honoraria. Anderson:C4 Therapeutics: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board; OncoPep: Other: Scientific founder ; Sanofi-Aventis: Other: Advisory Board; Janssen: Other: Advisory Board.