PASSIVE IMMUNOTHERAPY: TARGETING TUMOR CELLS CD38 in myeloma and - PowerPoint PPT Presentation

PASSIVE IMMUNOTHERAPY: TARGETING TUMOR CELLS CD38 in myeloma and beyond: groundwork & outlook Alessandra Larocca, MD, PhD Divisione di Ematologia 1 AOU Città della Salute e della Scienza University of Torino, Italy, EU

Disclosures: A Larocca Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Janssen-Cilag, Celgene, BMS, Amgen Scientific Advisory Board BMS This presentation may contain unregistered products or indications of investigational drugs, please check the drug compendium or consult the company

CD38 as a Therapeutic Target Flow cytometry of CD38 Structure of CD38 on myeloma cells CD38 - CD38 is a type II transmembrane glycoprotein, strongly expressed by myeloma cells - Role in cell signaling, cell adhesion, signal transduction, calcium homeostasis, production of adenosine (immunosuppressive effect) CD38 as a potential therapeutic antibody target for treatment of multiple myeloma (MM) Wikimedia Commons / Emw, CC-BY-SA-3.0: https://commons.wikimedia.org/wiki/File:Protein_CD38_PDB_1yh Lin P, et al. Am J Clin Pathol 2004;121;482.

Rationale for moAbs in MM

The impact of rituximab in diffuse large B-cell lymphoma Overall survival by treatment era Post-rituximab Pre-rituximab P < 0.0001 Can we find a monoclonal antibody that will change the course of myeloma in a similar way? Sehn ¡et ¡al. ¡J ¡Clin ¡Oncol ¡2005;23:5027-­‑5033 ¡

The bone marrow microenvironment influences tumor growth in MM In MM, the balance between tumor growth and tumor suppression is shaped by complex interaction between immune, non-immune, and malignant MM cells within the bone marrow microenvironment Tumor supporting Tumor Factors supporting tumor growth suppressive Angiogenesis Immunosuppression • IL-6 released by BMSCs, tumor-associated macrophages, and osteoclasts promotes MM cell proliferation, survival, and drug resistance • VEGF released by BMSCs and TAMs stimulates angiogenesis Factors suppressing tumor growth • CD8+ T cells and NK cells secrete IFN- ɣ and kill MM cells directly • Th1 CD4+ T cells may inhibit tumor growth Factors suppressing anti-MM immune cell activity • MDSCs and Tregs secrete immunosuppressive factors such as IL-10 and TGF- β Bone lysis • Th2 CD4+ T cells may promote tumor growth BMSCs, bone marrow stromal cells; DC, dendritic cell; Grz, granzyme; IFN, interferon; IL, interleukin; SC, myeloid derived suppressor cell; MM, multiple myeloma; NK, natural killer; pfp, perforin; TAM, tumor ssociated macrophage; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor; Treg, Guillerey C et al. Cell Mol Life Sci. 2016;73:156 ulatory T cell; VEGF, vascular endothelial growth factor.

Immune Evasion Plays a Critical Role in Myeloma Pathogenesis Immune System Tumor Immune Microenvironment dysregulation perturbation and immunosuppression Genetic alterations Disease progression

Rationale for Immunotherapy in Multiple Myeloma TARGETS FOR IMMUNOTHERAPY – Targeting MM cell surface Ags MoAb Anti-SLAMF7 MoAb Anti-CD38 – In MM patients, the normal immune system favors tumor proliferation Overcoming inhibitory immunosuppression Check-point inhibitors IMIDs Boosting immune effectors Adoptive cell therapy , immunomodulatory agent; MoAb, monoclonal antibody; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SLAMF7, signaling lymphocyt tion molecule family member 7. Hoyos V and Borrello I. Blood 2016; 128(13): 1

Targets for monoclonal antibody therapy in myeloma Cell ¡surface ¡targets ¡ Signalling ¡molecules ¡ IL-­‑6 ¡ RANKL ¡ DKK1 ¡ VEGF ¡ IGF-­‑1 ¡ SDF-­‑1 α ¡ BAFF, ¡APRIL ¡ Adapted from: Anderson KC. J Clin Oncol 2012;30:4

Three CD38 monoclonal antibodies Chimeric: Fully human: Isatuximab (SAR650984) Daratumumab (DARA) MOR202 (MOR) decreasing immunogenicity Adapted ¡from ¡Imai ¡& ¡Takaoka. ¡Nature ¡Reviews ¡Cancer ¡2006; ¡6: ¡7

Anti-CD38-monoclonal antibodies act through different modes of action in MM In vitro comparison of Daratumumab with analogs of CD38 antibodies plement-­‑dependent ¡cytotoxicity ¡ Nbody-­‑dependent ¡cell-­‑mediated ¡cytotoxicity ¡ grammed ¡cell ¡death ¡ Van de Donk N, et al. Blood. 2018;131(1 Nbody-­‑dependent ¡cell-­‑mediated ¡phagocytosis ¡

Preclinical evidence for anti CD38-moAbs in MM

CD38 expression correlates with cell death (patient samples) Patients divided into tertiles according to CD38 expression on their MM cells (n = 127 patient samples) Dose–response curve according to CD38 expression to evaluate different concentrations of daratumumab in ADCC and CDC assays. : ¡Complement-­‑dependent ¡cytotoxicity ¡ *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, not significant Nijhof et al. Leukemia 2015;29(10): C: ¡AnNbody-­‑dependent ¡cell-­‑mediated ¡cytotoxicity ¡

CD38 expression: determinants of efficacy Patients treated in GEN501 or SIRIUS (MMY2002) MFI, median fluorescence intensity CD38 Nijhof IS, et al. Blood 2016;128:9 PR, partial response

CD38 is rapidly reduced on MM cells from patients CD38 expression on MM cells in BM samples obtained from 21 patients, who were subsequently treated with daratumumab at a dose of 16 mg/kg in the GEN501 study. MFI, median fluorescence intensity CD38 < 0.01; ***P < 0.001; ****P < 0.0001 Nijhof ¡IS, ¡et ¡al. ¡Blood ¡2016;128: progressive disease

Dara combined with LEN or BORT in BORT and LEN-refractory MM Daratumumab induced significant levels of MM cell lysis in the BM-MNC from refractory MM patients. MM cell lysis was significantly improved from 29.7% with daratumumab alone to 39.4% upon combination of daratumumab-lenalidomide in patients were refractory to lenalidomide. ADCC assays 11/11 patients LEN-refractory 8/11 patients BORT-refractory The black circles represent the lenalidomide/bortezomib double- refractory patients Additive Synergy *P < 0.05; **P < 0.01; ***P < 0.001; ns, not significant Nijhof IS, et al. Clin Cancer Res. 2015;21(12):2802-2

Clinical evidences for anti CD38-moAbs in MM

Daratumumab Single Agent (GEN501 and SIRIUS*) Median N prior lines: 5 Refractory to Bortezomib and Lenalidomide: 87%; Refractory also to Pomalidomide: 55% Creatinine clearence > 30 (97%); age >75: 11% PR VGPR CR sCR 35 ORR = 31% 3% 30 2% 1% ≥ CR 13% ≥ VGPR 25 10% 20 15 10 18% 5 0 16 mg/kg CBR= 83% ed analysis dence interval; OS, overall survival; PFS, progression-free survival; ORR, overall response rate; PR, sponse; VGPR, very good partial response; CR, complete response, sCR, stringent CR; CBR, clinical Usmani S, et al. Oral presentation: ASH 2015; Orlando, FL. Abstra response (>SD).

Isatuximab monotherapy Median prior lines of therapy 5

MOR202

VD versus VD plus Daratumumab (CASTOR) Median follow-up: 26.9 months Median follow-up: 19.4 months DVd vs Vd DVd vs Vd DVd vs Vd Progression-free survival Progression-free survival-2 MRD negativity 5.2 x 4.8 x 6.0 x P <0.0001 P < 0.0001 P < 0.005 25 MRD-negative rate, % 19 20 15 12 10 5 4 5 2 1 0 10^-4 10^-5 10^-6 DVd Vd DVd Vd 10 –4 10 –5 10 –6 (n=251) (n=247) (n=251) (n=247) Sensitivity threshold Median PFS, mo 16.7 7.1 Median PFS2, mo NR 20.7 DVd (n=251) Vd (n=247) HR (95% CI) 0.32 (0.25–0.40) HR (95% CI) 0.47 (0.36–0.63) P value < 0.0001 P value < 0.0001 Spencer A, et al. Presented at ASH 2017 (Abstract 3145), poster presen Lentzsch S, et al. Presented at ASCO 2017 (Abstract 8036), poster presen S, progression-free survival; HR, hazard ratio, CI, confidence interval; m, months; d, low dose Weisel K, et al. Presented at EHA 2017 (Abstract S459), oral presen xamethasone; D, daratumumab; V, bortezomib; MRD, minimal residual disease

Rd versus Rd Daratumumab (POLLUX) Median follow-up: 32.9 months DRd vs Rd DRd vs Rd DRd vs Rd Progression-free survival Progression-free survival- 2 MRD negativity DRd Rd DRd Rd (n=286) (n=283) (n=286) (n=283) Median PFS, mo NR 17.5 Median PFS2, mo NR 32.3 HR (95% CI) 0.44 (0.34–0.55) HR (95% CI) 0.51 (0.38–0.67) P value <0.0001 P value <0.0001 Dimopoulos MA, et al. Presented at ASH 2017 (Abstract 739), oral present Lentzsch S, et al. Presented at ASCO 2017 (Abstract 8036), poster present S, progression-free survival; HR, hazard ratio, CI, confidence interval; P, P value; d, low Weisel K, et al. Presented at EHA 2017 (Abstract S459), oral presen se dexamethasone; D, daratumumab; R, lenalidomide; MRD, minimal residual disease.

Daratumumab-VMP vs VMP in NDMM transplant ineligible

Daratumumab-VMP versus VMP

Daratumumab-VMP versus VMP

Daratumumab-VMP versus VMP

CD38 in myeloma and beyond: groundwork & outlook