L6 Biological Therapy, Expand 2024 (PDF)

Antineoplastic Agents Cellular, biological and antibody therapy Tamer Elbayoumi, B.Pharm., M.S., Ph.D. Professor Dpt. of Pharmaceutical Sciences Glendale Hall 236-17 telbay@midwestern...

Antineoplastic Agents Cellular, biological and antibody therapy Tamer Elbayoumi, B.Pharm., M.S., Ph.D. Professor Dpt. of Pharmaceutical Sciences Glendale Hall 236-17 [email protected] Phone: (623)572-3592 Cancer Chemotherapy 3/5/2024 (PHIDG 1609)  Objectives Understand the principle of immuno-therapy Understand the molecular mechanism & targets of immuno- modulatory inhibitors (immune-checkpoint inhibitors). Differentiate between the various immuno-therapeutic agents according to their specific targets. Differentiate between various anticancer vaccines and cellular therapies according to their composition and specific targets. Highlight the clinical pharmacology of represented anticancer agents in each biological class Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 2  Pharmacologic classification of Chemotherapeutic agents Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 3  Immunotherapy: Using the Immune System to Treat Cancer The immune system’s natural capacity to detect and destroy abnormal cells (immuno-surveillance) should prevent the development of many cancers. However, cancer cells are sometimes able to avoid detection and destruction by the immune system: Reduce the expression of tumor antigens  harder to detect. Express surface proteins induce immune cell inactivation Induce cells in the surrounding microenvironment to release signals  suppress immune responses + promote tumor cell proliferation. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 4  Immunotherapies They increase the strength of immune responses against tumors, by: Either stimulate the activities of specific components of the immune system Or counteract signals produced by cancer cells that suppress immune responses. Still in clinical stages http://www.nature.com/nrc/journal/v15/n6/full/nrc3930.html Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 5  Immunotherapies: Immune Checkpoint Inhibitors PD-1 (Programmed cell CTLA-4 (cytotoxic T- death protein 1) lymphocyte- = CD279 (cluster of associated protein 4) differentiation 279) = CD152 (cluster of differentiation 152) "off" switch when bound to "off" switch ligands, PD-L1 when bound to (& PDL2) on CD80 or CD86 APCs & on the surface macrophages  of antigen- T-cell apoptosis presenting cells (APCs). PD-L1/2  Cancer Chemotherapy on cancer cells 3/5/2024 (PHIDG 1609) 6  Biological agents Immuno-stimulants/Immune System Modulators Immunotherapy: Cellular immunotherapy Naked monoclonal antibodies Immunotoxins Immuno-conjugates or Radio-immunotherapy Antibody–Drug Conjugates (ADC) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 7  Immunostimulants T cells are capable of attacking tumor cells. Failure of immune surveillance (T cells)  cancer development. Immunostimulants are non-specific agents  increase the body's immune defenses. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 8  Immunostimulants Aldesleukin (Proleukin®) Recombinant interleukin-2 (IL-2) product MOA: Causes activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia Increases production of cytokines including: tumor necrosis factor, IL-1, and gamma interferon  inhibit tumor growth. Therapeutic uses: Metastatic melanoma, metastatic renal cell carcinoma Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 9  Immunostimulants Denileukin diftitox (Ontak®) Recombinant IL-2 + diphtheria toxin SAR: Contains sequences for diphtheria toxin fragments and IL-2 MOA: Designed to direct the cytocidal action of the toxins to cells that express IL-2 receptor (Some leukemias & lymphomas, e.g. cutaneous T-cell lymphoma (CTCL) express the IL-2 receptor. Therapeutic uses: For recurrent or persistent CTCL that express CD25 component of the IL-2 receptor. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 10  Immunostimulants Recombinant Interferon alfa Recombinant Interferon -2a (Roferon-A) Therapeutic uses: Hairy cell leukemia AIDS-related Kaposi’s sarcoma Philadelphia chromosome positive chronic myelogenous leukemia (CML) [within 1year of diagnosis]. Interferon -2b (Intron A) Therapeutic uses: Hairy cell leukemia AIDS-related Kaposi’s sarcoma Malignant melanoma. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 11  Monocolonal antibodies ADCC = Antibody-Dependent Cellular Cytotoxicity CDC = Complement Dependent Cytotoxicity Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 12  Monocolonal antibodies (Cont.) Chimeric: Fc of human IgG combined with murine variable regions (Fab). Reduced HAMAs. De-immunized: immunogenic epitopes in murine variable domains  replaced with benign AA’s sequences  de-immunized Fab domain. Humanized: The antigen binding murine complementarity-determining regions are interspersed within the variable regions of the light and heavy chains of the Fab portion of the engineered antibody  NO HAMAs. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 13  Monocolonal antibodies Monoclonal antibody nomenclature: General Format= prefix-target-(origin)-mab -mab = monoclonal antibody (zu)mab = humanized monoclonal antibody (xi)mab = chimeric (mouse/human) monoclonal antibody (o)mab = mouse monoclonal antibody tu()mab = against a tumor ci()mab = against cardiovascular li(m) = against immune system vi(r) = against virus Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 14  Monocolonal antibodies So, just a simpler way of representation Just FYI Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 15  mAbs as Immune Checkpoint Modulators Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 16  Immune Checkpoint Modulators: Ipilimumab (Yervoy ) ® SAR/MOA: mAb blocks the activity of CTLA4 checkpoint “off-switch” (expressed on cytotoxic T lymphocytes)  blocks APC inhibitory signal (via CD80/86=B7.1/.2)  T-cell activation to recognize & destroy cancer cells. Therapeutic uses: For patients with late-stage melanoma that has spread or cannot be removed by surgery. Adjuvant therapy for stage 3 patients. FYI: Course of treatment = $120,000. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 17  Immune Checkpoint Modulators: Nivolumab (Opdivo®) & Pembrolizumab (Keytruda ) ® SAR/MOA: mAb blocks the activity of PD-1 checkpoint “off-switch” (expressed on activated T cells)  blocks inhibitory signal of PD-L1 on tumor  T-cell activation to recognize & destroy cancer cells. Therapeutic uses: Nivolumab  Unresectable or metastatic melanoma + squamous non-small cell lung (NSCL) cancer. Pembrolizumab certain advanced melanomas + NSCL cancer. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 18  Naked monocolonal antibodies Rituximab (Rituxan®) Genetically engineered chimeric murine/human monoclonal antibody SAR: Directed against the CD20 antigen of mature B lymphocytes. MOA: Binding of the Fab region to the CD20 antigen & the Fc domain  recruitment of immune effector functions to mediate cell lysis (induction of apoptosis)…i.e. ADCC & CDC. Eliminates both healthy and unhealthy B lymphocytes Therapeutic uses: For refractory or relapsed, low-grade or follicular, CD20- positive non-Hodgkin’s lymphoma. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 19 Naked monocolonal antibodies A little reminder of: Receptor tyrosine kinases (RTK) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 20  Naked monocolonal antibodies A little reminder of :Tyr. kinase receptors Epidermal growth factor receptor 1 Epidermal growth factor receptor 2 Platelet-derived growth factor receptor Fibroblast growth factor receptor 3 Protein of mesenchymal-epithelial hepatocyte growth transition factor factor receptor (HGFR) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 21  Naked monocolonal antibodies Trastuzumab (Herceptin®) MOA: Mediate antibody- dependent cellular cytotoxicity (ADCC) in cells overexpressing HER2. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 22  Naked monocolonal antibodies Trastuzumab (Herceptin®) MOA: Mediate antibody- dependent cellular cytotoxicity (ADCC) in cells overexpressing HER2. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 23  Naked monocolonal antibodies Trastuzumab (Herceptin®) Recombinant monoclonal antibody (humanized). SAR: Binds to extracellular domain of the human epidermal growth factor 2 protein (HER-2) (over-expressed in 25-30% of primary breast cancers). MOA: Mediate antibody-dependent cellular cytotoxicity (ADCC) in cells over-expressing HER2. Addition of trastuzumab to doxorubicin or Therapeutic uses: epirubicin   congestive heart failure TX of metastatic breast cancer (over-expressing HER-2 protein & received one or more chemotherapy regimens. First line therapy (as combo+ paclitaxel) for tumors over- expressing HER2 as first line therapy. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 24  Naked monocolonal Antibodies Cetuximab (Erbitux®) Immunoglobulin (IgG1) chimeric monoclonal antibody SAR: Exclusively targets, complexes, and inhibits the epidermal growth factor receptor (EGFR) and associated signaling cascade. MOA: Prevents autophosphorylation and activation of receptor-associated kinases  Inhibition of cell growth Induction of apoptosis ↓↓ pro-inflammatory cytokine & vascular growth factor production Therapeutic uses: Squamous cell carcinoma of head and neck, EGFR expressing colorectal cancer (metastatic)Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 25  Human vascular endothelial growth factor receptors (VEGFRs) Family of cell-surface TKRs: binding with VEGFs to initiate signal cascades to stimulate… VEGFR-1 (on hematopoietic stem cells + monocytes + vascular endothelial cells)  vasculogenesis + hematopoiesis + inflammatory cell recruitment VEGFR-2 (on vascular + lymphatic endothelial cells) angiogenesis (survival/proliferation & migration of endothelial cells) + FYI: vascular permeability Vasculogenesis  formation of a primitive vascular network during embryogenesis. Angiogenesis  formation of new blood vessels from pre-existing vessels Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 26  Human vascular endothelial growth factor receptors (VEGFRs) Family of cell-surface TKRs: binding with VEGFs to initiate signal cascades to stimulate… VEGFR-3 (only on lymphatic endothelial cells)  Lymph- angiogenesis … Owing to ligand-mediated cross- talk, NRP (neuropilin) receptors (1&2) act as co- receptors  Enhance VEGFRs signaling NRP-1/2 over-expression in tumors  angiogenesis + tumorigenesis + metastasis Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 27  Human vascular endothelial growth factors (VEGFs) VEGF-A: ↑↑ proliferation & migration of endothelial cells + Vascular permeability VEGF-B: angiogenesis + neuron survival VEGF-C&D: lymphatic sprouting, migration and proliferation = lymphangiogenesis PlGF: vasculogenesis + angiogenesis in ischemia/cancer Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 28  Naked monocolonal antibodies Bevacizumab (Avastin®) Recombinant humanized monoclonal IgG1 antibody SAR: Binds to soluble VEGF and inhibits the binding of VEGF-A to its receptors on the surface of endothelial cells MOA: By blocking VEGF, vascular endothelial cells do not proliferate  inhibit angiogenesis (i.e. inhibits survival/proliferation & migration of endothelial cells). Therapeutic uses: With 5-FU for first line therapy of metastatic colon and rectal cancers. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 29  Anti-VEGF drugs VEGF fusion soluble receptor/protein: Ziv-Aflibercept (Zaltrap®) - A recombinant fusion protein= extracellular domains of human VEGFR-1 + VEGFR-2 + fused to Fc portion of the human IgG1. - MOA = VEGF trap 1. High affinity binding to VEGF-A inhibiting BOTH VEGFR-1 + VEGFR-2 activation. 2. binds to VEGF-B & PlGF inhibiting VEGFR-1 activation. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 30  Anti-VEGF drugs VEGF fusion soluble receptor/protein: Ziv-Aflibercept (Zaltrap®) - MOA = VEGF trap 1. High affinity binding to VEGF-A inhibiting BOTH VEGFR-1 + VEGFR-2 activation. 2. binds to VEGF-B & PlGF inhibiting VEGFR-1 activation. Total effect = Prevents circulating angiogenic factors from binding to VEGFRs on endothelial cells  ↓↓ tumor neovascularization + Vascular Permeability - Indicated for metastatic colorectal cancer (CRC) that is resistant/progressed after FOLFOX regimen, in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 31  Anti-VEGFRs Full human monoclonal antibody (IgG1): Ramucirumab (Cyramza®) High affinity direct binding to the extracellular domain of VEGFR-2 blocking all VEGFR ligands (VGEF-A, -C & -D) inhibiting the angiogenesis pathways involved in development & progression of gastric cancers. Indications: Metastatic CRC, in combo with FOLFIRI single agent Stomach/gastroesophageal adenocarcinoma Adverse Rx: hypertension, diarrhea, and bleeding. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 32  Inhibitors of endothelial cell proliferation & migration Summary of VGEF-pathway mAb-targeted approaches Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 33  Naked monocolonal Antibodies Edrocolomab (Panorex®) Chimeric immunoglobulin (IgG2a) murine monoclonal antibody SAR: Exclusively targets human tumor-associated antigen epithelial cell adhesion molecule, EpCAM (17-1A). MOA: Induction of apoptosis via complement dependent cytotoxicity (CDC) Antibody-dependent cellular cytotoxicity (ADCC) Therapeutic uses: In colorectal carcinoma & metastatic breast cancer…(marginal to no benefit in stage III diseases). Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 34  Naked monocolonal Antibodies Tositumomab (Bexxar® = I131-tositumomab+ tositumomab) Murine IgG2a lambda monoclonal antibody (mouse) SAR: Against the CD20 antigen on the surface of B cells Conjugated with 131I radioisotope. MOA: Induction of apoptosis via complement dependent cytotoxicity (CDC) Antibody-dependent cellular cytotoxicity (ADCC) Ionizing radiation ( and ) from the conjugated 131I isotope Therapeutic uses: CD20 positive non-Hodgkins lymphoma that is refractory to rituximab Dosing is fairly complicated and is typically done in two phases (dosimetric & therapeutic). Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 35  Monoclonal Antibody Fragments Fragment antigen-binding (Fab) Single-Chain FV (scFV) antibody fragments CH-constant heavy VH-variable heavy VL-variable light VHH-variable heavy of heavy-chain-only antibodies: Camelid heavy chain-only antibody VNAR-variable Nurse Shark heavy of heavy-chain-only antibodies: IgNAR heavy chain-only antibody Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 36  Monoclonal Antibody Fragments Bispecific Antibody (BsAb) An antibody (Ab) containing two different antigen- binding sites within one molecule = BsAb Mosunetuzumab (Lunsumio ®) TX of adults with relapsed or refractory follicular lymphoma (EU & orphan-FDA) SAR: Against both CD20 antigen on the surface of B cells + CD3 antigen on T cells MOA: Focusing effector T cell activity to target close- by cancerous B cells for elimination  inducing direct cytotoxicity against CD20+ cancer cells. Therapeutic uses: Adults with relapsed or refractory follicular lymphoma (CD20+), after two or more TX Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 37  Monoclonal Antibody Fragments Bispecific T-Cell Engager (BiTE®) BiTE®= small fusion protein containing two different antibody binding sites Blinatumomab (Blincyto®) SAR: Simultaneously binds to: CD19 on cancer cells + CD3 on T cells  linking the T lymphocytes to CD19+ multiple myeloma (MM) cells MOA: BiTE binding  potentiates unstimulated T cells  inducing direct cytotoxicity Vs. CD19+ MM cells. Therapeutic uses: Relapsed or refractory MM adults who have received at least 4x prior TX Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 38  Which one of the following antibody-based therapies targets VEGFR-2 1. Trastuzumab 2. Cetuximab 3. Rituximab 4. Ramucirumab Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 39  Antibody–Drug Conjugates (ADCs) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 40  Immunotoxins = antibody directed therapy Gemtuzumab ozogamicin (Mylotarg®) MOA: (Trojan Horse) Following binding  antigen/antibody complex is internalized  Calicheamicin release conjugated calicheamicin  bind to the minor groove of DNA  strand breaks. H HN O N OCH3 O CH3 CH3 O N O N S H S CH3 CH3 O CH3 I O H3C O HO O O OCH3 OH O H3C H3C O OCH3 O Calicheamicin HO H3C H3CO OH H3CO O Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 41 Immunotoxins Gemtuzumab ozogamicin (Mylotarg®) Antibody-Drug Conjugate (ADC)=Antibody Directed Therapy SAR: Antibody to CD33 protein found on leukemic blasts & immature normal cells of myelomonocytic lineage. The cytotoxic agent is an enediyne antibiotic agent (calicheamicin) MOA: Following binding  antigen/antibody complex is internalized  release conjugated calicheamicin  bind to the minor groove of DNA  strand breaks. Therapeutic uses: CD33 positive acute myeloid leukemia (AML) in first relapse & not considered candidates for other cytotoxic therapy. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 42 Immunotoxins Brentuximab vedotin (Adcetris®) SAR: Antibody specific to CD30 protein expressed on classical Hodgkin lymphoma (HL) + anaplastic large cell lymphoma (sALCL). The cytotoxic moeity: is the antimitotic agent monomethyl 3x spacer auristatin E (MMAE) SH- Cleavable Attachment linker gp Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 43 Immunotoxins Brentuximab vedotin (Adcetris®) MOA: Following CD30-binding  brentuximab vedotin is internalized by endocytosis  endosome then fuse with lysosomes (lysosomal cysteine proteases, e.g. cathepsin B)hydrolysis of valine-citrulline linker  release of MMAE directly into tumor. Therapeutic uses: Relapsed/refractory Hodgkin's lymphoma +relapsed /refractory systemic anaplastic MMA: blocks microtubule polymerization large cell lymphoma. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 44  Radioimmunotherapy Ibritumomab (Zevalin®) Immunoglobulin (IgG1) chimeric monoclonal antibody+ tiuxetan (Chelator) + radioisotope (90Y or 111In) SAR: Against the CD20 antigen on the surface of B cells. MOA: Induction of apoptosis via complement dependent cytotoxicity (CDC) Antibody-dependent cellular cytotoxicity (ADCC) Ionizing radiation ( and ) from the conjugated isotope 90Y Diagnostic imaging with conjugated isotope 111In. Therapeutic uses: TX of B cell non-Hodgkin's lymphoma (NHL) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 45  Radioimmunotherapy Tositumomab (Bexxar® = I131-tositumomab+ tositumomab) Murine IgG2a lambda monoclonal antibody (mouse) SAR: Against the CD20 antigen on the surface of B cells Conjugated with 131I radioisotope. MOA: Induction of apoptosis via complement dependent cytotoxicity (CDC) Antibody-dependent cellular cytotoxicity (ADCC) Ionizing radiation ( and ) from the conjugated 131I isotope Therapeutic uses: CD20 positive non-Hodgkins lymphoma that is refractory to rituximab Dosing is fairly complicated and is typically done in two phases (dosimetric & therapeutic). Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 46  Common SE of immunotherapy Swelling Allergic reactions Flu like symptoms (e.g., fever, muscle aches, chills and fatigue Digestive problems Changes in blood pressure or myocarditis (heart inflammation) Kidney failure Leukopenia Infections (e.g., tuberculosis) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 47  According to antibody nomenclature guidelines, Rituximab (Rituxan®) is a ____ 1. cardiovascular-targeted chimeric monoclonal antibody. 2. cardiovascular-targeted humanized monoclonal antibody. 3. tumor-targeted chimeric monoclonal antibody. 4. tumor-targeted humanized monoclonal antibody 5. none of the above. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 48  Anticancer vaccines Preventive (or prophylactic) vaccines: Intended to prevent cancer from developing in healthy people Treatment (or therapeutic) vaccines: Intended to treat an existing cancer, by strengthening the body’s natural defenses against the cancer. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 49  Anticancer vaccines Prophylactic vaccines: ≠ Human PapillomaVirus (HPV) & Cancer: Transmitted via skin-to-skin contact >100 strains of HPV, 40 of which  through sexual contact High risk HPV cause 5% of cancers worldwide Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 50  Anticancer vaccines Prophylactic vaccines: Gardasil®: To prevent anal, cervical, vulvar, and vaginal cancer caused by human papillomavirus (HPV) types 16 and 18 + genital warts caused by HPV types 6 and 11, caused by virus-associated lesions (i.e. quadri-valent vaccine). Gardasil® 9 = same 4 HPV types (6, 11, 16, 18) + 5 additional HPV types (31, 33, 45, 52, 58) causing anal + oropharyngeal and other head & neck cancers. Used in males and females aged 9-45 years. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 51  Anticancer vaccines Prophylactic vaccines: Cervarix®: To prevent cervical cancer caused by human papillomaviruses (HPV) types 16 and 18 , plus caused by virus-associated lesions (i.e. Bi-valent vaccine). Used in females aged 9-26 years Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 52  Anticancer vaccines Therapeutic Vaccines Sipuleucel-T (Provenge®): FDA approved in 2010. approved for use in men with metastatic prostate cancer & is indicated for asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Extended survival by 4.1 months (IMPACT Phase III trial). The treatment costs about $100K. Designed to stimulate an immune response to the over- expressed prostate cancer cell antigen (prostatic acid phosphatase, PAP). Sipuleucel-T is the first therapeutic cellular immunotherapy. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 53  Anticancer vaccines Therapeutic Vaccines: Sipuleucel-T (Provenge®): Supplied as an IV infusion, containing a minimum of 50 million autologous CD54+ cells, activated with PAP-GM- CSF. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 54  Anticancer vaccines Therapeutic Vaccines: Sipuleucel-T (Provenge®): Supplied as an infusion, containing a min. of 50 mil. autologous CD54+ cells activated with PAP-GM-CSF, designed for intravenous administration. The recommended course of therapy is three complete doses, given at approx. 2-week intervals. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 55  Anticancer vaccines Therapeutic Vaccines: Talimogene Laherparepvec/ T-VEC (Imlygic ): First-in-class, “live attenuated” herpes simplex virus type 1 (HSV-1)–based oncolytic immunotherapy HSV1 is genetically modified  oncolytic virus enable selective replication in tumor cells with a tolerable safety profile + expression of GM- CSF for systemic immune stimulation. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 56  Anticancer vaccines Therapeutic Vaccines: Talimogene Laherparepvec/ T-VEC (Imlygic ): First-in-class, “live attenuated” herpes simplex virus type 1 (HSV-1)–based oncolytic immunotherapy Approved for: local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery TDA: Tumor-derived antigen APC: Antigen-presenting cell Cancer Immunol. Immunother. 66(10), 1249–1264 (2017) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 57  Anticancer vaccines Therapeutic Vaccines: Talimogene Laherparepvec/T-VEC (Imlygic ): MOA= Intratumoral immunotherapy: 1- Direct tumor cell lysis (via replicating virus) 2- Stimulation of local response in tumor microenvironment + systemic immune response in distant metastases (via expression of GM-CSF) T-cell activation against distant metastasis Advantages: ↑↑↑ intra-tumoral bioavailability ↓↓ total required dose ↓↓ systemic exposure = ↓↓ AEs enables combo therapy different MOA & routes of administration. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 58  Adoptive cell transfer (ACT) = cellular immunotherapy Tumor-Infiltrating Lymphocyte (TIL) Therapy Engineered T Cell Receptor (TCR) Therapy Chimeric Antigen Receptor (CAR) T Cell Therapy Natural Killer (NK) Cell Therapy Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 59  Tumor-Infiltrating Lymphocyte (TIL) Therapy TILs can be found between the tumor cells, without actual penetration or action on the tumor cells. Ex-vivo Naturally occurring T-cells (already infiltrating patients’ tumors)  harvested (selectively based on CD3+) activated (with IL- 2) expanded  re-infused into patients (+IL-2)  seek & destroy tumors 22-day protocol  durable regression of metastatic melanoma (50% pts) Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 60  Engineered T Cell Receptor (TCR) Therapy T-cells may not recognize target tumor cannot be sufficiently activated and expanded. Isolate pt’s T-cells equipped with new T cell receptor (to target specific cancer antigens) activated (with IL-2) expanded  re-infused into patients (+IL-2) after conditioning/non- myeloablative (NMA) therapy (5FU + Fludarabine) seek & destroy tumors. Imp. To remember: TCRs are composed of one α chain + one β chain. TCR recognize antigens that have been processed and presented by the patient’s own MHC molecules Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 61  Chimeric Antigen Receptor (CAR) T Cell Therapy Isolate pt’s T-cells transfect with new genes to express CAR on T-cells  expanded ex-vivo  re-infused into patients (+IL-2) after conditioning/non- myeloablative (NMA) therapy (5FU + Fludarabine) seek & - destroy tumors. Imp. To remember: - CARs are artificial receptors - constructed by linking the Fab of antibody + intracellular signaling chains (such as CD3-zeta) + other signaling moieties. - CARs recognize antigens presented on tumor cells, but DO NOT need to be MHC- restricted. Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 62  Chimeric Antigen Receptor (CAR) T Cell Therapy Tisagenlecleucel (Kymriah®) A genetically-modified autologous T-cell immunotherapy CD19-targeted CAR-T cells: CD19-targeting Fv-antibody region CD28: co-stimulatory domain CD3ζ: cytoplasmic activation domain Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 63  Chimeric Antigen Receptor (CAR) T Cell Therapy Tisagenlecleucel (Kymriah®) Approved in Oct. 2017 for TX of pediatric and young adult patients (≤25yr) B-cell precursor ALL - refractory or in second or later relapse. Jun.2018: TX of diffuse large B- cell lymphoma (DLBCL). Toxicities: Cytokine release syndrome (CRS) threatening neurological events (encephalopathy/delirium) Life Cancer Chemotherapy 3/5/2024 (PHIDG 1609) 64  CAR T Cell Therapy: B Cell Maturation Antigen (BCMA)-directed Anti-BCMA CAR T: BCMA = TNF- receptor superfamily Expressed by mature B lymphocytes  implicated in MM BCMA specifically bind to the TNF(ligand) superfamily, member  activation of NF-κB + MAPK  ↑↑ anti-apoptotic proteins  ↑↑ survival of MM cells soluble BCMA (sBCMA) = from direct shedding of membrane BCMA  sBCMA is considered a biomarker for MM patients & their therapy MM still incurable disease: modest efficacy (ORR 26–34%, median PFS