Immune-mediated Mechanism Of Action Research Articles

Outcomes by occurrence of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC).

4004 Background: Immune checkpoint inhibitor (ICI) studies have shown an association between the occurrence of imAEs and outcomes. In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S. STRIDE and D had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and recommended for approval by the European Medicines Agency; D is approved in Japan. This exploratory analysis assessed the association between imAEs and outcomes in HIMALAYA. Methods: Safety was assessed in participants (pts) who received ≥1 dose of STRIDE (T 300 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]) or D (1500 mg Q4W). imAEs were AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action with no found alternate etiology. Median OS (mOS) and OS rates were estimated using the Kaplan–Meier method. OS hazard ratios (HRs) and 95% CIs were calculated using Cox modeling, with imAEs as a time-varying covariate and stratified by etiology (HBV/HCV/others), ECOG (0/1), and macro-vascular invasion (yes/no) for pts with vs without imAEs of any grade. Pts with >1 imAE were counted once. Results: In total, 388 pts (STRIDE) and 388 pts (D) were included in the analysis. Any grade imAEs, Grade 3 or 4 imAEs, and imAEs leading to discontinuation occurred in 139 (35.8%), 49 (12.6%), and 22 (5.7%) pts, respectively for STRIDE and 64 (16.5%), 25 (6.4%), and 10 (2.6%) pts, respectively for D. imAEs requiring high-dose steroids (≥40 mg prednisone or equivalent daily) occurred in 78 (20.1%) pts for STRIDE and 37 (9.5%) pts for D. An improvement in OS was seen with STRIDE in pts with imAEs vs pts without (HR, 0.73; 95% CI, 0.56–0.95). OS rates at 6, 12, and 24 months (mo) were higher for STRIDE in pts with imAEs vs pts without. The association between imAEs and OS was less clear for D and may be limited by small pt number. In a landmark analysis of pts with vs without imAEs within 6 mo of STRIDE (n=307) or D (n=287), OS HRs (95% CIs) were 0.65 (0.47–0.90) and 1.39 (0.95–2.04), respectively. Conclusions: In HIMALAYA, imAEs with STRIDE or D were manageable and generally low grade. In this exploratory analysis, the occurrence of imAEs was associated with improved OS for STRIDE, generally consistent with findings for other ICIs. Clinical trial information: NCT03298451 . [Table: see text]

Pharmaconutraceutical Chondroguard®TRIO – a new ideology for the prevention of musculoskeletal diseases and nutritional support for patients with osteoarthritis and nonspecific back pain: an assessment of clinical options. Resolution of the First Multidisciplinary Bilateral Russia – Uzbekistan Expert Council

On April 1, 2023, experts presented a resolution of the First Multidisciplinary Bilateral Russia–Uzbekistan Expert Council, dedicated to innovations in the prediction and personalized prevention of degenerative-dystrophic diseases of the joints and spine, and the possibilities of using the new pharmaconutraceutical Chondroguard®TRIO, the components of which (chondroitin sulfate, glucosamine sulfate, undenatured collagen type II – NK-II type) can be attributed to active compounds that modify the course of the disease (Disease-modifying osteoarthritis drugs, DMOADs) through structure-modifying and immune-mediated mechanisms of action. The evidence base for the efficacy and safety of the use of the main components of the new pharmaconutraceutical Chondroguard®TRIO (chondroitin sulfate, glucosamine sulfate, type NK-II) for the prevention and adjunctive therapy of osteoarthritis and nonspecific back pain is presented in the clinical recommendations of foreign specialized associations: Osteoarthritis Research Society International (OARSI), European Alliance of Associations for Rheumatology (EULAR), European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), American College of Rheumatology (ACR), Russian Clinical Guidelines of the Russian Ministry of Health, as well as in numerous interventional and observational clinical studies.

From seaside to bedside: Current evidence and future perspectives in the treatment of breast cancer using marine compounds.

To date, only few marine natural compounds have been proved to be active in breast cancer (BC). The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents (eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders—trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs). Notably, eribulin is the only approved cytotoxic drug for the treatment of advanced BC (ABC), while cytarabine has a limited indication in case of leptomeningeal diffusion of the disease. Also plocabulin showed limited activity in ABC but further research is needed to define its ultimate potential role. The available clinical data for both trabectedin and lurbinectedin are of particular interest in the treatment of BRCA-mutated tumours and HR deficient disease, probably due to a possible immune-mediated mechanism of action. One of the most innovative therapeutic options for the treatment of BC, particularly in TNBC and HER2-positive BC, are ADCs. Some of the ADCs were developed using a specific marine-derived cytotoxic molecule as payload called auristatin. Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics.

Race for the Cure: From the Oldest to the Newest Monoclonal Antibodies for Multiple Myeloma Treatment.

Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel drugs with immune-mediated mechanisms of action. Some of these compounds, such as the anti-cd38 daratumumab and isatuximab, the anti-slamf-7 elotuzumab, and the antibody-drug conjugate belantamab-mafodotin, have been tested in large clinical trials and have now fully entered the real-life management. The bispecific T-cell engagers are under investigation with promising results, and other satisfactory data is expected from the application of nanotechnologies. The perfect timing to introduce these drugs in the sequence of treatment and their adverse events represent new challenges to be addressed, and further experience is required to improve their use.

Abstract 2981: Loss of the small GTPase RHOA enhances lymphomagenesis and impairs the activity of lenalidomide in mantle cell lymphoma

Abstract The small GTPase Ras homolog family member A (RHOA) is one of the most extensively investigated members of the Rho GTPase family, that acts as a molecular switch controlling a wide variety of signal transduction pathways. Although RHOA has long been implicated in malignant transformation in solid tumors, recent evidences have demonstrated its tumor suppressor activity in different subgroups of B-cell non-Hodgkin lymphoma (B-NHL). Here, using a panel of 11 cell lines covering the most common and/or aggressive B-NHL subtypes, we observed that the lowest mRNA and protein levels of RHOA are found in mantle cell lymphoma (MCL), the most aggressive entity with a median overall survival of 5-7 years. Depletion of RHOA expression and activity was carried out in the two RHOA+ MCL cell lines, REC-1 and Z-138, by CRISPR/Cas9-mediated gene edition followed by RHOA pulldown activation assay. In RHOA knockout (KO) subclones, cell proliferation was increased by 40%, in association with a 10-fold increase in mitotic index and a 3-fold potentiation of cell migration, as assessed respectively by CellTitter-Glo assay, histone H3-pSer10 labeling and Transwell assay, thus suggesting a tumor suppressor role of RHOA in MCL malignancy. Comparative RNA-seq analysis of RHOAWT and RHOAKO MCL subclones then highlighted a crucial role of RHOA and its downstream signaling in the control of MCL cell proliferation, cell cycle and cell migration. Interestingly, the immunomodulatory drug lenalidomide has previously shown to regulate such processes and to be clinically active in patients with relapsed/refractory MCL. In a co-culture system associating RHOAWT MCL cells with peripheral blood-derived effector cells, we observed that lenalidomide treatment facilitated the formation of immunological synapse, as revealed by simultaneous immunodetection of effector T cells, target B cells and perforin, and by quantification of lactate dehydrogenase (LDH) release. Conversely, lenalidomide exhibited minimal effect in the RHOAKO MCL co-cultures, as shown by a 30-40% decrease in the formation of immune synapse and a 4-fold decrease in LDH secretion. Taken together, these data provide the first insight into the tumor suppressive activity of RHOA in MCL and into its requirement for the immune-mediated mechanism of action of lenalidomide in this disease. Ongoing in vivo validation studies will be presented. Citation Format: Juliana C. Santos, Marcelo L. Ribeiro, Gael Roue. Loss of the small GTPase RHOA enhances lymphomagenesis and impairs the activity of lenalidomide in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2981.

Abstract P1-18-19: Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Abstract Background: Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with increased therapeutic efficacy of trastuzumab/pertuzumab-based neoadjuvant therapy (NT) in patients (pts) with HER2-positive breast cancer (BC). Subcutaneous (SC) trastuzumab has non-inferior efficacy to intravenous (IV) administration, with a similar safety profile. Interestingly, SC trastuzumab has been observed to be more immunogenic than IV trastuzumab and act at different immunologic levels. Therefore, by modifying the modality of administration of trastuzumab, it could be possible to interfere with different immune pathways and exert a favorable immunomodulation in HER2-positive BC. Methods: In this non-comparative, phase II, neoadjuvant, randomized study, pts were eligible if they had previously untreated, histologically confirmed, locally advanced, inflammatory, or early-stage HER2-positive BC. Pts were treated with FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) q21 × 3 cycles. Then, they were randomly assigned (1:1) to receive: docetaxel (75 mg/m2) plus pertuzumab (840 mg loading dose (LD), then 420 mg) plus IV trastuzumab (8 mg/kg LD, then 6 mg/kg) q21 × 4 cycles (arm A) or, docetaxel plus pertuzumab plus SC trastuzumab (fixed dose of 600 mg) q21 × 4 cycles (arm B). After surgery, pts received trastuzumab q21 × 14 cycles using the same formulation (SC or IV) of the preoperative phase. The primary endpoint was the rate of stromal TILs (sTILs) on residual disease after surgery. Tumor biopsy and posttreatment surgical samples were centrally analyzed for TILs. Blood samples were also collected during NT for tumor-specific lymphocyte cell activity analysis. Feasibility, efficacy and safety were also evaluated. ClinicalTrials.gov: NCT03144947. Results: Between November 2016 and September 2017, according to an adaptive Simon's two-stage optimal design, we enrolled 65 pts, of whom two were deemed ineligible for the study. Thus, 63 pts (31 in arm A and 32 in arm B) were assessed for the primary and secondary endpoints. The pathologic complete response (pCR; no invasive tumor in breast and axilla) rates were 64.5% (95% CI, 47-81) in arm A, and 59.4% (95% CI, 42-76) in arm B. The most common adverse events of grade 3 or higher were neutropenia (15 [48.4%] pts in arm A, and 11 [34.4%] in arm B), neurotoxicity (1 [3.2%], and 2 [6.2%], respectively), and diarrhea (1 [3.2%], and 1 [3.1%], respectively). There were no events of congestive heart failure. At surgery, 11 pts in arm A and 13 pts in arm B were evaluable for TIL analysis. The median value of sTILs (7.5%) on pre-treatment tumor biopsies was used as the cut-off value, and high sTIL levels were observed in 27.3% and in 46.1% of residual tumors after treatment arm A and B, respectively. There was a positive correlation between pretreatment sTILs and PD-L1 expression on stromal immune cells (Kendall’s τ =0.80). Interestingly, a significant inverse correlation was observed between PD-L1 expression on pretreatment sTILs and the T cell co-receptor CD3 expressed on posttreatment sTILs (Pearson’s ρ = -0.70). This finding was particularly evident in the arm B group (ρ = -0.85). Conclusions: NT with either SC or IV trastuzumab in combination with pertuzumab and chemotherapy had a significant effect on sTIL expression at surgery. In particular, the SC trastuzumab-based arm exerted the most relevant enrichment of sTILS in posttreatment residual tumors. These findings suggest a role for the SC administration of trastuzumab in determining favorable variations of host immune response parameters among pts with HER2-positive early BC who had residual disease after NT. Citation Format: Antonino Musolino, Stefania Gori, Elisabetta Cretella, Alessandra Marabese, Luigi Cavanna, Antonio Frassoldati, Giancarlo Bisagni, Chiara Casarini, Emilio Bria, Luisa Carbognin, Elena Fiorio, Alba A Brandes, Claudio Zamagni, Lorenzo Gianni, Alberto Zambelli, Filippo Montemurro, Michele Tognetto, Renata Todeschini, Giuseppe Maglietta, Gabriele Missale, Enrico M Silini. Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-19.

Effect of plinabulin, a novel late-clinical stage immunotherapeutic agent on the adaptive and innate immune system.

8 Background: Plinabulin (Plin) is a small molecule Dendritic Cell modulator, which in the presence of antigen, increases T-cell proliferation in an antigen-dependent manner marrow. The addition of Plin to Docetaxel (Doc) improved mOS with 4.6 months vs Docetaxel monotherapy, and prolonged DoR with more than 1 year (p < 0.05), which is indicative of an immune-mediated mechanism of action (Mohanlal, ASCO-SITC 2017). Neutrophils are our first line of innate immune defense against foreign invaders. We previously reported that Plinabulin prevents chemotherapy (Chemo) Induced Neutropenia (CIN) in patients receiving Doc or TAC throughout the cycle (Doc, Doxorubicin, Cyclophosphamide) (Blayney ASH 2018, St Gallen 2019). Here we analyzed the onset time of neutrophil increase following Plin administration. In addition, we analyzed the impact of Plin on plasma haptoglobin, which is an acute phase protein with anti-inflammatory effects together with immune-enhancing effects and is an integral part of innate immunity (Kristiansen Nature 2001). Methods: Absolute neutrophil count (ANC) and haptoglobin data were analyzed from Phase 2 study BPI-2358-106 (NCT03294577) with 10 (n = 15), 20 (n = 15) and 30 mg/m2 (n = 12) Plin in Breast Cancer patients receiving TAC. Plin was administered on Day 1. ANC and Haptoglobin were analyzed by a Central Laboratory (Covance), from blood draws at predose, and post-dose Plin at Day 2,3,6,7,8,9,10,11,12,13 and 15, and changes relative to predose value were evaluated. Results: Plin dose-dependently increased ANC within 1 day (P < 0.001) and Haptoglobin within 3 days (P < 0.03) of dosing. Mean haptoglobin (P < 0.0005) and ANC (P < 0.001) levels increased with ~two-fold vs baseline levels. ANC levels remained increased for approximately 1 week and haptoglobin levels for > 3 weeks. Conclusions: Based on Plinabulin’s ability to stimulate the innate system, together with its previously reported evidence as a potent activator of the adaptive immune system (Mohanlal, ASCO-SITC 2017), it is concluded that Plinabulin is a potent stimulator of the adaptive and innate immune system. Clinical trial information: NCT03294577.

Inter-Cell Networking Profiling Enables Comprehensive Characterization of Immune-Mediated Activity of Anti-CD38 Therapy through Ex-Vivo Analysis of Multiple Myeloma Patients

Inter-Cell Networking Profiling Enables Comprehensive Characterization of Immune-Mediated Activity of Anti-CD38 Therapy through Ex-Vivo Analysis of Multiple Myeloma Patients

Abstract 1710: DKN-01, a therapeutic DKK1 neutralizing antibody, has immune modulatory activity in nonclinical tumor models

Abstract Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt signaling modulator DKK1 is expressed in a variety of tumor types and elevated levels frequently correlate with poor survival. DKK1 promotes tumor growth by stimulating proliferation, metastasis, and angiogenesis, and has been implicated in contributing to an immune suppressive tumor microenvironment. DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and selectivity. It is currently being evaluated clinically as a monotherapy and in combination in a variety of solid tumors. Here we describe further characterization of the mechanism of action of DKN-01 and demonstrate immune mediated anti-tumor activity in nonclinical models. A murine version of DKN-01 (mDKN-01) has efficacy in a syngeneic melanoma B16 tumor model. However, mDKN-01 is unable to impede B16 tumor growth in NSG immunodeficient mice, indicating that a functioning immune system is required for antibody activity. Furthermore, preliminary data suggest that mDKN-01 is targeting a myeloid derived suppressor cell population in the tumor microenvironment. These data support an immune mediated mechanism of action of DKN-01 and provide a rationale for clinical development in combination with immunotherapy agents. The first clinical study evaluating DKN-01 in combination with pembrolizumab has initiated enrollment in patients with relapse/refractory esophagogastric malignancies. Citation Format: Michael Haas, Heidi Heath, Yinyuan Wu, Xinjun Zhang, Cynthia Sirard, Xi He, Walter Newman, Michael Kagey. DKN-01, a therapeutic DKK1 neutralizing antibody, has immune modulatory activity in nonclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1710.

Abstract 3683: Melphalan stimulates dendritic cell and CD8+ T cell expansion by inducing immunogenic cell death in melanoma cells

Abstract Background: Regional hyperthermic perfusion with the alkylating agent melphalan is a treatment option for patients with metastatic melanoma confined to the limbs or the liver. Following a single perfusion, tumors often decrease gradually in size during several months, suggesting an immune-mediated mechanism of action, in addition to the direct cytotoxic effects of melphalan. This study was designed to characterize the immunogenic effects of melphalan. Materials and methods: We have established an in vitro model of regional hyperthermic perfusion where human melanoma cell lines are exposed to melphalan at 40oC for 1 h, thus mimicking the currently employed clinical protocol. The melphalan-exposed melanoma cells were analyzed for markers of immunogenic cell death and were co-cultured with peripheral blood mononuclear cells (PBMCs) in the presence or absence of IL-2. The number and activation status of various immune populations were analyzed by flow cytometry. Results: Melphalan exposure triggered the expression of several immune-related markers on melanoma cells, including calreticulin, MHC class I, Hsp70 and PD-L1. Melphalan-treated, but not untreated melanoma cells, triggered an increase in dendritic cell (DC) numbers along with a dramatic expansion of CD8+ T cells in co-cultured PBMCs. The expanded CD8+ T cells showed an activated phenotype with the majority of cells belonging to the effector memory subtype. Conclusions: Melanoma cells exposed to melphalan undergo immunogenic cell death and trigger DC expansion with subsequent expansion and activation of CD8+ T cells. We propose that these events may contribute to the anti-tumor efficacy of regional hyperthermic perfusion with melphalan in metastatic melanoma. Citation Format: Junko Johansson, Roberta Kiffin, Per Lindnér, Peter Naredi, Roger Olofsson Bagge, Anna Martner. Melphalan stimulates dendritic cell and CD8+ T cell expansion by inducing immunogenic cell death in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3683. doi:10.1158/1538-7445.AM2017-3683

Outcomes Following Lenalidomide for Relapsed/Refractory Mantle Cell Lymphoma Patients at Risk of Bleeding Events Because of Multiple Comorbidities or Treatment: A Post-Hoc Subgroup Analysis of the SPRINT (MCL-002) Trial

Outcomes Following Lenalidomide for Relapsed/Refractory Mantle Cell Lymphoma Patients at Risk of Bleeding Events Because of Multiple Comorbidities or Treatment: A Post-Hoc Subgroup Analysis of the SPRINT (MCL-002) Trial

MAGNIFY: Phase IIIb Randomized Study of Lenalidomide Plus Rituximab (R2) Followed By Lenalidomide Vs. Rituximab Maintenance in Subjects with Relapsed/Refractory Follicular, Marginal Zone, or Mantle Cell Lymphoma

▪Background:Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination.Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of subjects with grades 1-3b FL (including transformed lymphoma [TL]), MZL, or MCL who received >=1 prior therapy and had stage I-IV, measurable disease (>1.5 cm). Subjects received 12 cycles of R2 induction, consisting of oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Subjects with stable disease (SD) or better after induction were then were randomized 1:1 to R2 vs. rituximab maintenance. Stratification to the 2 maintenance arms was based on histology (FL grade 1-3b and TL vs. MZL vs. MCL), number of prior lines of antilymphoma therapy (<=2 vs. >2), and age (<65 vs. >=65 years).Maintenance R2 consisted of lenalidomide 10 mg/day, d1-21/28, cycles 13-30 plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (Arm A). Rituximab maintenance alone was on the same schedule (Arm B). Subjects receiving R2 maintenance after 18 cycles are eligible to continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (optional per subject and/or investigator discretion) until disease progression as tolerated. The primary endpoint isprogression-free survival (PFS) comparing maintenance arms using a two-sided test with alpha=0.05 and HR=0.67. Secondary endpoints include safety, overall survival, and response rates. Efficacy is evaluated per modified 1999 IWG criteria and safety per NCI CTCAE version 4.03.Results: As of Jan 11, 2016, 135 subjects have been enrolled, including 91 (67%) with FL, 24 (18%) with MZL, 19 (14%) with MCL, and 1 (1%) with TL. At the time of enrollment, subjects had a median age of 66 years (range, 41-91); 81% had stage III/IV disease. Subjects had received a median of 2 prior therapies (range, 1-10), with 36% refractory to rituximab (defined as SD/PD to or PR/CR for <6 months with prior rituximab). The most common prior regimens were rituximab (41%), BR (25%), R-CHP (14%), R-CHOP (11%), and R-CVP (7%). At data cut-off, 45 (33%) subjects discontinued treatment before the maintenance period. Primary reasons for discontinuation of lenalidomide and/or rituximab, respectively, were due to AEs in 16 (12%) and 14 (10%) subjects, PD in 15 (11%) subjects for either treatment, withdrawal by subject in 6 (4%) and 7 (5%) respectively, and death 3 (2%) in either treatment. In the safety population (n=124), treatment-emergent adverse events (AE) during induction that led to dose reduction/interruption of lenalidomide or rituximab occurred in 55% or 24% of subjects, respectively, mainly due to neutropenia for lenalidomide and infusion-related symptoms for rituximab. The most common grade 3/4 AEs during induction were 27% neutropenia, 9% leukopenia, 6% thrombocytopenia, and 5% fatigue. 11 subjects have died (5 due to PD, 3 AEs, 3 other). At a median duration of 23.1 weeks (range, 0.1-51.1) of induction, 90 subjects were evaluable for response. Best responses to induction were 56 (62%) subjects with ORR, 8 (9%) CR, 12 (13%) CRu, 36 (40%) PR, and 22 (24%) SD. Responses with R2 treatment were observed in all histologies (Table 1). At data cut-off, 19 subjects have completed induction and 18 have proceeded to maintenance (n=7 R2, n=11 rituximab alone). Continued study and follow-up are ongoing to enroll more subjects in the induction and maintenance arms.Conclusions: R2 induction therapy shows favorable activity and a tolerable safety profile in subjects with advanced-stage, relapsed/refractory FL, MZL, MCL, and TL. Continued study is ongoing to determine the effect of R2 vs. rituximab maintenance following 1 year of R2 induction. [Display omitted] DisclosuresAndorsky:Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI: Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Bitran:Oncology Specialists: Employment. Melear:Texas Oncology: Employment. Foon:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Llorente:Celgene: Employment. Li:Celgene: Employment, Equity Ownership. Sharman:Genentech: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy.

Abstract B023: Antibody blockade of Semaphorin 4D enhances infiltration of APC and CD8 T cells and reduces immune suppression to facilitate immune-mediated tumor rejection

Abstract Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease in several human tumors. We have reported a novel role for SEMA4D in modulating the tumor microenvironment (TME) to exclude activated antigen presenting cells and cytotoxic T lymphocytes so as to promote tumor growth; this effect can be reversed by antibody blockade. Purpose: Characterize immune-related anti-tumor activity mediated by antibody neutralization of SEMA4D, as a single agent and in combination with other immunomodulatory therapies, including immune checkpoint inhibition. Methods: Blockade of SEMA4D with monoclonal murine antibody was evaluated in murine melanoma and colon cancer models. Immune response in pre-clinical models was characterized by immunohistochemistry, flow cytometry, functional assays, as well as cytokine, chemokine and gene expression analysis. Therapeutic activity was evaluated in various preclinical models. A Phase I trial in patients with advanced solid tumors was completed. Results: SEMA4D restricts migration of macrophage cell lines and promotes expansion of suppressive tumor associated macrophage (TAM) and myeloid derived suppressor cells (MDSC) in vitro. Strong expression of SEMA4D at the invasive margins of actively growing tumors in vivo modulates the infiltration and polarization of leukocytes in the TME. In preclinical models, antibody neutralization disrupted the SEMA4D gradient at the invasive margin, which correlated with recruitment of activated APCs and T lymphocytes into the TME. This was accompanied by a significant shift towards increased Th1 cytokines (IFNΓ, TNFA) and CTL-recruiting CXCL9 chemokine, with concurrent reduction in Treg-, MDSC- and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5). Accordingly, an increase in Teff:Treg ratio (3x, p&amp;lt;0.005) and CTL activity (4x, p&amp;lt;0.0001) was observed. MDSCs were significantly reduced in both tumor and blood following treatment. Nanostring gene expression analysis of on-treatment tumors confirms an increase in the gamma-inflammatory immune gene signature that was predictive of ORR and PFS in KEYNOTE 001 (Ribas, ASCO 2015), including significant increases in CXCL9, Gzmb, CCR5, Stat1, Lag3, Ptprc (NK function), Ciita (MHC presentation), Pdcd1 (PD-1), Itga1 (adhesion, leukocyte function). The coordinated anti-SEMA4D induced changes in the tumoral immune context are associated with durable tumor rejection and immunologic memory in preclinical colon, breast, and melanoma models. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can be further enhanced by combination with other immunotherapies, including immune checkpoint inhibitors and chemotherapy. Strikingly, the combination of anti-SEMA4D with anti-CTLA-4 acts synergistically, with maximal increase in survival (110% tumor growth delay, p&amp;lt;0.01) and complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p&amp;lt;0.01). SEMA4D antibody treatment was well tolerated in nonclinical and clinical studies; including a Phase I multiple ascending dose trial in patients with advanced refractory solid tumors. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. Progression free survival strongly correlated with elevated baseline lymphocyte counts (r = 0.6133), consistent with an immune mediated mechanism of action for VX15/2503, a humanized IgG4 anti-SEMA4D antibody. Conclusion: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. Phase 1b/2a trials of combination therapy with immune checkpoint inhibition are planned. Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Ekaterina Klimatcheva, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark J. Paris, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Antibody blockade of Semaphorin 4D enhances infiltration of APC and CD8 T cells and reduces immune suppression to facilitate immune-mediated tumor rejection [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B023.

Abstract A07: Plinabulin: Evidence for an immune-mediated mechanism of action

Abstract The purpose of this study was to investigate the evidence for an immune-mediated mechanism of action for plinabulin. Plinabulin, a novel compound for use in oncology, is an inhibitor of tubulin polymerization, induces direct tumor cell apoptosis (Nicholson et al, 2006), inhibits angiogenesis and activates the JNK pathway (Singh et al, 2011) and is in Phase 3 trials for NSCLC (Bazhenova, 2015). The methods for the in vitro and in vivo studies performed are described by Martin et al (2014) and Müller et al (2014). Recent data from in vitro studies demonstrate that plinabulin enhances immune responses as (1) it increases dendritic cell maturation as evidenced by elevated levels of CD40, MHCII, CD80 and CD86 and (2) the release of pro-inflammatory cytokines such as IL-1beta, IL-6 and IL12p40. These increases were similar to those observed with LPS. Paclitaxel and etoposide were inactive in these assays. In the MC-38 syngeneic colon tumor model in the C57BL/6 immunocompetent mouse, plinabulin (7.5 mg/kg, IP, BIW) significantly enhanced the therapeutic effect of combined PD-1/CTLA-4 inhibition on tumor volume, with a maximal effect occurring between days 13-20 after initiation of treatment. When tumor weight was measured at necropsy, plinabulin significantly enhanced the effect of both PD-1 inhibition and combined PD-1 + CTLA-4 inhibition. In this regard, evidence has been provided that agents which interfere with tubulin polymerization (e.g. ansamytocin-P3, dolastatin-10), but not microtubule stabilizing agents (e.g. docetaxel, paclitaxel) promote anti-tumor immunity as demonstrated by dendritic cell maturation and enhanced T-cell activation both in vitro and in vivo. In addition, the microtubule depolymerizing agents act synergistically with immune checkpoint inhibitors (Martin et al, 2014, Müller et al, 2014). These data indicate an immune mediated mechanism of action of plinabulin and provide the basis for initiating a clinical trial of plinabulin with the PD-1 mAb Nivolumab in metastatic NSCLC (Yeh et al, 2015). Citation Format: George Kenneth Lloyd, Philipp Mueller, ALfred Zippelius, Lan Huang. Plinabulin: Evidence for an immune-mediated mechanism of action. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A07.

Abstract 4888: Antibody blockade of semaphorin 4D breaks down stromal barriers to enhance tumoricidal immune infiltration, supporting rational immunotherapy combinations

Abstract Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer; increased expression correlates with poor prognosis. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the tumor microenvironment (TME), SEMA4D is expressed strongly at the invasive margin and modulates the infiltration and spatial distribution of leukocytes, suppressing anti-tumor activity. Neutralization of SEMA4D was evaluated for effects on immune activity and tumor growth in preclinical models, incorporating single agent and combination treatments with other immunotherapies, including immune checkpoint blockade inhibitors. The safety and tolerability of humanized anti-SEMA4D antibody VX15/2503 was assessed in a Phase I clinical trial. RESULTS: SEMA4D restricts migration of myeloid cells expressing cognate PLXNB1/2 receptors, determined using trans-well migration assays and IHC of in vivo tumors. Antibody neutralization disrupted the SEMA4D gradient at the invasive margin, which correlated with recruitment of activated APCs and T lymphocytes into the TME, and significant shift toward increased Th1 cytokines (IFNg, TNFa) and CTL-recruiting CXCL9 chemokine, with concurrent reduction in Treg- and M2-macrophage promoting chemokines (CCL2, CXCL1, CCL17). Accordingly, an increase in Teff:Treg ratio (3x, p&amp;lt;0.005) and CTL activity (4x, p&amp;lt;0.0001) was observed. This orchestrated change in the tumoral immune context was associated with durable tumor rejection and immunologic memory in preclinical colon, breast, and melanoma models. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can be further enhanced by combination with other immunotherapies, including immune checkpoint inhibitors and chemotherapy. Strikingly, the combination with antibody to CTLA-4 acts synergistically, with maximal increase in survival (110% tumor growth delay, p&amp;lt;0.01) and complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p&amp;lt;0.01). SEMA4D antibody treatment was well tolerated in nonclinical and clinical studies; including a Phase I multiple ascending dose trial in patients with advanced refractory solid tumors. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. Progression free survival strongly correlated with elevated baseline lymphocyte counts (r = 0.6133), supporting an immune mediated mechanism of action for VX15/2503. CONCLUSION: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. A phase 1b/2 trial of combination therapy with an immune checkpoint inhibitor is planned. Citation Format: Elizabeth E. Evans, Holm Bussler, Sebold Torno, Crystal Mallow, Christine Reilly, Maria Scrivens, Ekaterina Klimatcheva, Laurie A. Winter, Renee Kirk, Alan Howell, Leslie Balch, John E. Leonard, Mark Paris, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Antibody blockade of semaphorin 4D breaks down stromal barriers to enhance tumoricidal immune infiltration, supporting rational immunotherapy combinations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4888.

Abstract 2346: Intratumoral administration of OncoVEXmGM-CSF results in local innate immune alterations and induces systemic anti-tumor effects in syngeneic mouse tumor models

Abstract Talimogene laherparepvec, is a modified oncolytic herpes simplex virus type-1 (HSV-1) designed to selectively replicate in tumors and to initiate a systemic immune response to target cancer cells. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors, with lytic cell destruction promoting the local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally and is designed to recruit and stimulate antigen presenting cells to further enhance systemic antitumor immune response. While available evidence suggests that talimogene laherparepvec can induce effects in distant tumors via an immune-mediated effect, additional mechanistic evidence is being sought to help better understand the putative systemic effect. For preclinical mechanism of action studies we employed OncoVEXmGM-CSF, an HSV-1 virus modified in the same manner as talimogene laherparepvec except that murine GM-CSF is expressed. We utilized this virus to further dissect the underlying innate and adaptive immunity following viral administration in syngeneic tumor models. Intratumoral administration of OncoVEXmGM-CSF into established murine tumors induced regressions in the injected lesion but also resulted in significant anti-tumor effects in contralateral (uninjected) lesions. We have previously demonstrated by immunohistochemistry that the systemic effects observed in the contralateral lesions are not driven by systemic spread of the virus, but instead correlate with the infiltration of CD3+ T cell populations. Here we report the full phenotypic characterization of immune infiltrates by flow cytometry in both the injected and contralateral lesions. In a time-course fashion, this characterization revealed the initial infiltration of the injected tumor by innate effector cells and a concomitant induction of a potent type I interferon response. This in turn drives the local release of proinflammatory cytokines and chemokines, resulting in the recruitment of adaptive immune subsets to the injected tumor and enhancing systemic anti-tumor reactivity. Additionally, both the primary oncolytic replication of the virus and the activation of type I interferon pathway are directly correlated with STING activity. In conclusion, in vitro and in vivo observations suggest that intratumoral injection of OncoVEXmGM-CSF activates multiple immune-mediated mechanisms of action leading to T-cell activation and induction of anti-tumor immunity in mice. Citation Format: Keegan Cooke, Karen Fitzgerald, Becky Yang, Juan Estrada, Brian Belmontes, Pedro Beltran, Achim K. Moesta. Intratumoral administration of OncoVEXmGM-CSF results in local innate immune alterations and induces systemic anti-tumor effects in syngeneic mouse tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2346.

Abstract A119: Antibody blockade of Semaphorin 4D neutralizes barrier to immune infiltration and facilitates immune-mediated tumor rejection

Abstract Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, we describe a novel immunomodulatory function of SEMA4D in regulation of immune cell infiltration and activity in the tumor microenvironment (TME). Purpose: Characterize immune-related and anti-tumor activity mediated by antibody neutralization of SEMA4D, as a single agent and in combination with other immunomodulatory therapies. Methods: Blockade of SEMA4D with monoclonal murine antibody was evaluated in subcutaneous models, as well as an orthotopic ERBB2+ breast carcinoma syngeneic model. Anti-tumor immune response in pre-clinical models was characterized by selective in vivo immune cell depletions, as well as immunohistochemistry, flow cytometry, and functional assays. The safety and tolerability of a humanized anti-SEMA4D antibody VX15/2503 was assessed in Phase I clinical trials in oncology. Results: SEMA4D restricts migration of macrophage cell lines in vitro. Strong expression of SEMA4D at the invasive margins of actively growing in vivo tumors modulates the infiltration and spatial distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient and facilitates recruitment of potent antigen presenting cells and T lymphocytes into the TME, shifting the balance of cytokines toward increased Th1 and reduced immunosuppressive cytokines. This orchestrated change in the tumor architecture was associated with durable tumor rejection and immunologic memory in preclinical models. Immune-mediated tumor rejection may enhance the disruption of ERBB2 transactivation with SEMA4D receptors, which has been reported for ERBB2 and Met oncogenes. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can also be further enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival, with significant 58% increase in tumor regression and maximal increase in survival, as compared to monotherapy. Treatment with anti-SEMA4D antibodies was well tolerated in nonclinical and clinical studies, including completion of a Phase I prospective multiple ascending dose trial in patients with advanced refractory solid tumors. Weekly doses of between 0.3 and 20 mg/kg were administered; no MTD was determined. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. Progression free survival correlated with elevated baseline lymphocyte counts, supporting an immune mediated mechanism of action for VX15/2503. Conclusion: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. A phase 1b/2a trial of combination therapy with immune checkpoint inhibition is planned. Citation Format: Elizabeth E. Evans, Holm Bussler, Sebold Torno, Crystal Mallow, Laurie A. Winters, Christine Reilly, Ekaterina Klimatcheva, Janaki Veeraraghavan, Alan S. Jonason, Maria Scrivens, Renee Kirk, Alan Howell, Leslie Balch, John E. Leonard, Mark Paris, Terrence L. Fisher, Ernest S. Smith, Maurice Zauderer. Antibody blockade of Semaphorin 4D neutralizes barrier to immune infiltration and facilitates immune-mediated tumor rejection. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A119.

Abstract 4287: Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity

Abstract Talimogene laherparepvec is an investigational oncolytic immunotherapy based on a modified herpes simplex virus type-1 (HSV-1) immunotherapy designed to selectively replicate in tumors and to initiate an anti-tumor immune response. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors. Iterative replication of virus within permissive tumor tissue results in lytic cell destruction and local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally such that it can recruit and stimulate antigen presenting cells which, in addition to relevant tumor-derived antigens, are required for the initiation of a systemic antitumor immune response. The talimogene laherparepvec-induced immune mediated mechanism of action in both the virus-injected and distant tumors have yet to be fully understood therefore, we evaluated viral replication, tumor cell lysis, and the changes in immune cell populations in both the injected and distant tumors using syngeneic contralateral tumor models. Animals received a single intratumoral dose of the murine surrogate of talimogene laherparepvec (OncoVEXmuGM-CSF), which induced regression in the majority of virus-injected tumors and tumor growth inhibition/regression in the contralateral (uninjected) tumors. HSV-1 antigen was only detected by IHC in the virus-injected tumor and not the contralateral tumor (and no other tissues). Virally-mediated tumor destruction (oncolysis) was also localized to only the virus-injected tumor. In preliminary experiments, morphometric analysis of the tumor tissue revealed that the percent area of CD3+ and CD8+ lymphocytes were significantly increased in both the virus-injected and contralateral tumors compared to the formulation control mice. In addition, the percent area occupied by CD103+ cells (a marker found on potent cytotoxic T cell stimulating dendritic cells) was increased in the virus-injected tumor compared to the contralateral tumor and the tumors in the control animals. Although cellular infiltration was increased in both virus-injected and contralateral tumors and was inversely correlated with tumor volume, the decreased volume of injected tumors was attributed to viral oncolysis. Taken together these data supports that talimogene laheparepvec activates a systemic T cell mediated anti-tumor immune response. Citation Format: Julia Piasecki, Jim Rottman, Tiep Le, Rafael Ponce, Courtney Beers. Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4287. doi:10.1158/1538-7445.AM2015-4287

Regulating Cytokine Function Enhances Safety and Activity of Genetic Cancer Therapies

Genetic therapies, including transfected immune cells and viral vectors, continue to show clinical responses as systemically deliverable and targeted therapeutics, with the first such approaches having been approved for cancer treatment. The majority of these employ cytokine transgenes. However, expression of cytokines early after systemic delivery can result in increased toxicity and nonspecific induction of the immune response. In addition, premature immune-mediated clearance of the therapy may result, especially for viral-based approaches. Here, it was initially verified that cytokine (interleukin (IL)2) or chemokine (CCL5) expression from a systemically delivered oncolytic virus resulted in reduced oncolytic activity and suboptimal immune activation, while IL2 also resulted in increased toxicity. However, all these limitations could be overcome through incorporation of exogenous regulation of cytokine or chemokine transgene function through fusion of a small and externally controllable destabilizing domain to the protein of interest. Regulation allowed an initial phase without cytokine function, permitting enhanced delivery and oncolytic activity before activation of cytokine function and a subsequent phase of enhanced and tumor-targeted immunotherapeutic activity. As a result of this exogenous regulation of cytokine function, both oncolytic and immune-mediated mechanisms of action were optimized, greatly enhancing therapeutic activity, while toxicity was significantly reduced.

Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials

9034 Background: The monoclonal antibody ipilimumab targets cytotoxic T-lymphocyte antigen-4. The most common AEs associated with ipilimumab are irAEs, and both antitumor and irAE responses likely reflect its immune-mediated mechanism of action. In this report, a potential association between disease control (DC) or overall survival (OS) and irAEs in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in 3 Phase II clinical trials was explored. Methods: Across 3 Phase II studies (CA184008, 022, and 007), ipilimumab (10 mg/kg) was given every 3 weeks (Q3W) x 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (wk) 24 (maintenance). In study 022, pts were randomized to 0.3, 3, and 10 mg/kg groups, whereas study 008 was a single-arm trial of ipilimumab 10 mg/kg. In study 007, ipilimumab 10 mg/kg was administered either with placebo or daily prophylactic budesonide. Disease control (CR/PR/SD) was evaluated using modified World Health Organization (mWHO) and immune- related response criteria (Hodi FS, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3008). Association between DC and grade 0/1 vs. grade ≥2 irAEs was examined (studies 007, 008, and 022). Association between OS and irAEs which developed within 12 wks of ipilimumab treatment was also explored using landmark analyses from Day 81 (studies 008 and 022). Results: Across the 3 phase II studies, the rate of DC by mWHO in pts with grade 0/1 irAEs was 20–24% and in pts with grade ≥2 irAEs was 34–43%. The number of pts with DC was higher among those who experienced an irAE compared with those who did not, but DC was not statistically significantly associated with grade 0/1 vs grade ≥2 irAEs. For pts who lived up to Day 81 in studies 008 and 022, median OS (95% CI) from Day 81 was 14.8 mo (10.0–21.7) for any irAE and 8.21 mo (5.29–13.7) for no irAE within 12 weeks; median OS was 13.6 mo (5.78-NR) for any grade ≥2 irAE and 11.3 mo (7.95–15.8) for no grade ≥2 irAE within 12 weeks. Conclusions: DC and survival benefits with ipilimumab are observed among pts that develop an irAE and among pts that do not develop an irAE. Thus, pts who do not experience an irAE may still demonstrate clinical benefit with ipilimumab. [Table: see text]