Fundamentos de Terapia Biológica e Inmunoterapia del Cáncer, Hospital del Mar

Fonaments de Terapia Biologica i Immunoterapia del Cancer

Joan Albanell Servei d'Oncologia Medica Programa de Recerca en Cancer Hospital del Mar Parc de Salut MAR Barcelona upf. Universitat Pompeu Fabra Barcelona21st Edition HARRISON'S ® PRINCIPLES O F INTERNAL MEDICINE LOSCALZO FAUCI KASPER HAUSER VOLUME 1 Hospital del Mar Parc de Salut MAR Barcelona Mc Graw Hill LONGO JAMESON

Agentes Moleculares Dirigidos Aprobados por la FDA para el Tratamiento del Cáncer

Tabla 72-2: Algunos Agentes Moleculares Dirigidos Aprobados por la FDA para el Tratamiento del Cáncer

DRUG MOLECULAR TARGET DISEASE MECHANISM OF ACTION DRUG MOLECULAR TARGET DISEASE MECHANISM OF ACTION Ivosidenib IDH1 AML IDH1 inhibitor Gilteritinib FLT3 AML FLT3 inhibitor Idelalisib PI3K-delta CLL, SLL, FL Inhibits PI3k-delta, preventing proliferation and inducing apoptosis Alpelisib PIK3CA Breast cancer with a PIK3CA mutation Inhibits PIK3CA

Anticuerpos Monoclonales

Trastuzumab HER2/neu (ERBB2) Breast cancer, gastric cancer Binds HER2 on tumor cell surface and induces receptor internalization Pertuzumab HER2/neu (ERBB2) Breast cancer Binds HER2 on tumor cell surface at distinct site from trastuzumab and prevents binding to other receptors Cetuximab EGFR Colon cancer, squamous cell carcinoma of the head and neck Binds extracellular domain of EGFR and blocks binding of EGF and TGF-ox; induces receptor internalization. Potentiates the efficacy of chemotherapy and radiotherapy Larotrectinib, entrectinib NTRK Cancers with NTRK mutation Competitive inhibitor of ATP binding site of the tyrosine kinase domain of NTRK Axitinib VEGFR1-3 RCC Competitive inhibitor ATP binding site of tyrosine kinase domain VEGF receptors Erlotinib EGFR NSCLC, pancreatic cancer Competitive inhibitor of the ATP-binding site of the EGFR Afitinib EGFR (and other HER family) NSCLC Irreversible inhibitor of ATP-binding site of HER family members Osimertinib EGFR (1790M) NSCLC Inhibits EGFR mutations including 1790M mutant NSCLC Dacomitinib EGFR NSCLC (exon19 deletion/exon 21 LB58R) Inhibits EGFR mutant lung cancer Erdafitinib, pemigatinib FGFR2, FGFR3 Urothelial (erdafitinib), cholangiocarcinoma (pemigatinib) Breast cancer Competitive inhibitor of the ATP-binding site of HER2 Crizotinib, ceritinib, alectinib, brigatinib, lorlatinib ALK NSCLC Inhibitor of ALK tyrosine kinase Crizotinib, entrectinib Palbociclib, ribociclib, abemaciclib CDK4/6 Breast Inhibitor of ROS1 tyrosine kinase Inhibitor of CDK4/6 Bortezomib, carfilzomib, ixazomib Proteasome Multiple myeloma Inhibits proteolytic degradation of multiple cellular proteins Vemurafenib, dabrafenib BRAF Melanoma Inhibitor of serine-threonine kinase domain of V600E mutant of BRAF Encorafenib MEK CRC Inhibits BRAFV600E mutation; used in combination with cetuximab Dinutuximab Glycolipid GD2 Neuroblastoma (pediatric) Immune-mediated attack on GD2-expressing cells Daratumumab CD38 MM Binds to CD38 on MM cells causing apoptosis by antibody- dependent or compliment-mediated cytotoxicity Elotuzumab SLAMF7 MM Activating NK cells to kill MM cells Blocks PDGFRox activity Olaratumab PDGFRc Soft tissue sarcomas Blinatumomab CD19 and CD3 Ph-relapsed precursor B-cell ALL Binds CD19 on ALL cells and CD3 on T cells; immune attack on CD19-expressing cells

Conjugados Anticuerpo-Quimioterapia

Brentuximab vedotin CD30 Hodgkin's disease, anaplastic lymphoma Delivery of chemotherapeutic agent (MMAE| to CD30-expressing tumor cells Ado-trastuzumab emtansine HER2 Breast cancer Delivery of chemotherapeutic agent emtansine to HER2-expressing breast cancer cells Fam-trastuzumab HER2 Breast cancer, gastric cancer Delivery of chemotherapeutic agent deruxtecan to HER2- expressing breast cancer cells

Células CAR-T

Tisagenlecleucel, axicabtagene ciloleucel CD19 ALL (tisagenlecleucel), DLBCL/ high-grade BCL (axicabtagene ciloleucel) Targeted T cells to protein on surface of malignant cells Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BCL, B-cell lymphoma; CAR-T, chimeric antigen receptor T cells; CLL, chronic lymphocytic leukemia; CRC, colorectal cancer; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; FDA, U.S. Food and Drug Administration; FGFR, fibroblast growth factor receptor; FL, follicular lymphoma; Fit-3, fms-like tyrosine kinase-3; GIST, gastrointestinal stromal tumor; HDAC, histone deacetylases; MCL, mantle cell lymphoma; MM, multiple myeloma; MSI, microsatellite instability; MTC, medullary thyroid cancer; mTOR, mammalian target of Rapamycin; MZL, mantle zone lymphoma; NK, natural killer; NSCLC, non-small-cell lung cancer; PARP, poly-ADP ribose polymerase; PDGFR, platelet-derived growth factor receptor; PLGF, placenta growth factor; PML-RARox, promyelocytic leukemia-retinoic acid receptor-alpha; PNET, pancreatic neuroendocrine tumors; PTL, peripheral T-cell lymphoma; RCC, renal cell cancer, t(15;17), translocation between chromosomes 15 and 17; SCLC, small-cell lung cancer, SLL, small lymphocytic lymphoma; TGF-c, transforming growth factor-alpha; VEGFR, vascular endothelial growth factor receptor; WM, Waldenström's macroglobulinemia. Parc de Salut MAR Barcelona (Continued)

Capítulo 72: Biología de la Célula Cancerosa

Tabla 72-2: Agentes Moleculares Dirigidos Aprobados por la FDA para el Tratamiento del Cáncer (Continuación)

Alemtuzumab CD52 Chronic lymphocytic leukemia and CD52-expressing lymphoid tumors Immune mechanisms Bevacizumab VEGF Colorectal, lung cancers, RCC, glioblastoma Ziv-aflibercept VEGFA, VEGFB, PLGF Colorectal cancers Inhibits angiogenesis by high-affinity binding to VEGFA, VEGFB, and PLGF Bomucinumah MEGED Gastric colorortal luna canones Inhihite anninnonosis hu hindina to VEGED Ipilimumab CTLA-4 Melanoma, HCC, MSI-high colorectal cancer Blocks CTLA-4, preventing interaction with CD80/86 and T-cell inhibition Nivolumab, pembrolizumab PD-1 Blocks PD-1, preventing interaction with PD-L1 and T-cell inhibition Atezolizumab, durvalumab, avelumab PD-L1 NSCLC, urothelial cancer, SCLC (durvalumab), HCC (atezolizumab), Merkel cell cancer (avelumab) Denosumau Breast, prostate Trametinib, Cobimetinib MEK Melanoma Inhibitor of serine-threonine kinase domain of MEK CabozanunIo RET, MET, VEGFR MIC, RCC Compeuuve inhibitor of ATP-binding site of tyrosine kinase domain of multiple kinases, including VEGFR2 and RET Capmatinib MET NSCLC with MET exon14 deletions Vandetanib RET, VEGFR, EGFR MTC Competitive inhibitor of ATP-binding site of tyrosine kinase domain of multiple kinases, including RET Selpercatinib RET NSCLC, MTC, RET fusion thyroid cancer Inhibitor of RET, VEGFR1, VEGFR2 tyrosine kinases Temsirolimus mTOR RCC Competitive inhibitor of mTOR serine-threonine kinase Everolimus mTOR RCC, PNET Binds to immunophilin FK binding protein-12, which forms a complex that inhibits mTOR kinase Vorinostat, romidepsin, belinostat HDAC CTCL/PTL HDAC inhibitor, epigenetic modulation Panobinostat Ruxolitinib JAK-1, 2 Myelofibrosis Competitive inhibitor of tyrosine kinase Vismodegib Hedgehog pathway Basel cell cancer (skin) Inhibits smoothened in hedgehog pathway Lenvatinib Multikinase inhibitor (VEGFR, FGFR, PGFR-O, others) RCC, thyroid cancer, HCC Competitive inhibitor of ATP-binding site of tyrosine kinase domain of multiple kinases Olaparib, rucaparib, niraparib, talazoparib PARP BRCA mutant ovarian, breast, prostate, pancreas cancers; not all agents approved for all cancers Venetoclax BCL-2 CLL (with 17p deletion) Inhibits BCL-2 and enhances apoptosis Ibrutinib, acalabrutinib Bruton tyrosine kinase (BTK) CLL, MCL, MZL, SLL, WM Inhibitor of BTK 513 All-trans retinoic acid PML-RARa oncogene Acute promyelocytic leukemia M3 AML, t(15;17) Inhibits transcriptional repression by PML-RARO Imatinib Bcr-Abl, c-Abl, c-Kit, PDGFR-a/B Chronic myeloid leukemia, GIST Blocks ATP binding to tyrosine kinase active site Ripretinib C-Kit, PDGFR-o GIST Inhibits tyrosine kinase activity Dasatinib, nilotinib, ponatinib, bosutinib Bcr-Abl (primarily) Chronic myeloid leukemia Blocks ATP binding to tyrosine kinase active site Sunitinib C-Kit, VEGFR-2, PDGFR-B, Fit-3 GIST, RCC, PNET Inhibits activated c-Kit and PDGFR in GIST; inhibits VEGFR in RCC and probably in PNET Sorafenib RAF, VEGFR-2, PDGFR-c/B, Fit-3, c-Kit RCC, hepatocellular carcinoma (HCC), differentiated thyroid cancer, desmoid Targets VEGFR pathways in RCC and HCC. Possible activity against BRAF in thyroid cancer Regorafenib VEGFR1-3, TIE-2, FGFR1, KIT, RET, PDGFR Colorectal cancer, GIST, HCC Competitive inhibitor ATP binding site of tyrosine kinase domain multiple kinases including VEGFR Panitumumab Necitumumab EGFR Colon cancer EGFR Squamous NSCLC Similar to cetuximab but fully humanized rather than chimeric Binds EGFR Rituximab CD20 B-cell lymphomas and leukemias that express CD20 Multiple potential mechanisms, including direct induction of tumor cell apoptosis and immune mechanisms Inhibits angiogenesis by high-affinity binding to VEGF Inhibits tyrosine kinase of FGFR Lapatinib, tucatinib HER2/neu ROS1 NSCLC Melanoma, head and neck cancer, NSCLC, SCLC, Hodgkin's disease, urothelial cancer, RCC, HCC, gastric cancer, MSI-high cancers, endometrial cancer Blocks PD-L1, preventing interaction with PD-1 and T-cell inhibition HDAC MM HDAC inhibitor, epigenetic modulation Inhibits PARP and DNA repair Hospital del Mar

Capacidades Adquiridas de la Célula Neoplásica

Cel. cancerosa Fibroblastos

1. Autosuficiencia en señales proliferativas (activacion oncoger es )
2. Insensibilidad a señales anti-proliferativas (no responden a fenos)
3. Evasión de la apoptosis
4. Inmortalidad replicativa (división infinita)
5. Angiogenesis mantenida
6. Invasión tisular y metástasis

Cel. Immunol. Cel. endoteliales Hospital del Mar Parc de Salut MAR Barcelona Hanahan & Weinberg, Cell 100, 2000

Hallmarks of Cancer: The Next Generation

Douglas Hanahan1,2,* and Robert A. Weinberg3 ;* We defined hallmarks to be acquired functional capabilities

• that contribute to the manifestation of the disease
• that are operative chronically, rather than during the carefully orchestrated tasks of cells and organs in the body IMP EGFR inhibitors Cyclin-dependent kinase inhibitors Aerobic glycolysis inhibitors Sustaining proliferative signaling Evading growth suppressors Immune activating anti-CTLA4 mAb Deregulating cellular energetics Avoiding immune destruction Proapoptotic BH3 mimetics Resisting cell death 4 8 Enabling replicative immortality Telomerase Inhibitors Gannma Tumor- Hallmarks with clinically approved drugs targeting their mechanisms

El diagrama muestra los "Hallmarks of Cancer" de Hanahan y Weinberg, que describen las capacidades funcionales adquiridas por las células tumorales. Además, incluye terapias dirigidas clínicamente aprobadas para inhibir mecanismos clave, como inhibidores de EGFR, PARP, telomerasa y VEGF. Se enfatiza la importancia de la evasión inmune, la angiogénesis y la inflamación tumoral en la progresión del cáncer.

Figure 6. Therapeutic Targeting of the Hallmarks of Cancer

Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of the enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks. Cell 2011