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Cancer Immunotherapy
The document presents an overview of cancer immunotherapy, including its history, various types such as cytokine injections, vaccination strategies, immune checkpoint blockade, and adoptive cell transfer. It discusses mechanisms of action, the effects of these therapies on patient survival, and highlights future prospects like combination therapies and systemic infusion of oncolytic viruses. Overall, it emphasizes the evolving strategies to enhance immune response against cancer.
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Cancer Immunotherapy
- 1. Therapeutic Prospects ofCancer Immunotherapy Presenter: Dr Pranav Sopory All India Institute of Medical Sciences New Delhi 1
- 2. Contents 1. Our ImmuneSystem 2. Introduction to Cancer Immunotherapy 3. Types of Immunotherapies 4. Future prospects 5. Summary 2
- 3. Our Immune System:Classification 3
- 4. Our Immune System 4 CD8+ CTL killing a Sq. cell carcinoma cell. 3 mechanisms of CTL activation: 1. Direct stimulation via MHC-TCR 2. Co-stimulation 3. Cytokine mediated stimulation
- 5. Tolerance • Failure tomount an immunological response. • 2 types: 1. Tumor microenvironment: Expresses IL-10, TGF- β: dampen T Cell functions 2. Pathogenic conversion: of CTL to immunosuppressive cell populations (eg. T-reg) 3. Overexpression: Too many Ag expressed: T cell cant bind 4. Camouflage: Alterations in antigen expression 5. Immune checkpoint modulation: Produce PD-L1 Natural/Self Tolerance Prevents autoimmune diseases Induced Tolerance Promotes Cancer growth 5 Immunoediting leads to Tolerance
- 6. HELP OUR IMMUNESYSTEM FIGHT CANCER Aim of Cancer Immunotherapy 6
- 7. History • 1893: Cellular& molecular mechanisms of cancer unknown • William Coley: SERENDIPITOUS DISCOVERY • Sarcoma patients: Spontaneous remission after Strep. Pyogenes infection. • Developed “Coley’s toxin”: S. Pyogenes + S. Marcescens • Produced remarkable recoveries. • S/E: Full blown infections + Surgical site contamination. 7
- 8. Types of CancerImmunotherapies Types Mechanism Examples 1. Non specific Immune stimulation A. Cytokine injections: • Interleukin injections B. Infectious disease vaccines • BCG vaccine for bladder cancer 2. Vaccination strategies A. Dendritic cell Approach • Sipuleucel-T B. Oncolytic Virus therapy • T-VEC 3. Immune checkpoint blockade A. Programmed Death receptor inhibitor • Pembrolizumab 4. Adoptive cell transfer A. CAR T-cell therapy • Tisagenlecleucel 8
- 9. 1. (a) Cytokineinjections: Interleukins IL-2 injections • Result: significant tumor regression in patients • It promotes effector T cell (CTL) proliferation Approved: • Metastatic Renal Cell Carcinoma (1992) • After nephrectomy • Conventional chemotherapy doesn't work 9
- 10. 1. (b) BCGvaccine for bladder cancer Bacillus Calmette-Guerin (BCG) • Intravesical: put directly into the bladder through a catheter • Early-stage bladder cancer (STCC). • Treatment is usually started a few weeks after a TURBT and is given once a week for 6 weeks • Urine: Increased levels of IL-2. 10
- 11. 2. Vaccination strategies •Mimic the strategy used against infectious diseases • AIM: Break Tolerance: Prime the immune cells to fight the tumor cells • Approach: Non-Specific Vaccines Antigen Specific Vaccines Requires no knowledge of immunogenic components Target antigen: Cancer specific Elicits all types of response Elicits CD8+ CTL response Eg.: 1. Tumor lysates 2. Irradiated tumor cells Eg.: 1. Dendritic Cell Vaccine 2. Oncolytic Vaccine • CANVAXIN: Irradiated, polyvalent, whole-cell Melanoma vaccine. (Phase II: 2006) • SIPULEUCEL – T • T-VEC 11
- 12. 2. (a) Vaccinationstrategies: Dendritic Cell approach Ideal Vaccine: • Triggers maturation of DCs to a state where they can promote production of tumor reactive CD8+ CTL Why Dendritic cells? • Most powerful APCs • Have co-stimulatory action also 12
- 13. 2.a Vaccination strategies:Sipuleucel-T Target Ag: Prostatic Acid Phosphatase (PAP) • Enzyme syn. by prostate epithelial cells • Physiological role: not understood • ↑ amount in Metastatic CA Prostate • Unlike PSA: marker only in High-risk CA Prostate Indication: • Metastatic, Castration Resistant (Hormone-refractory) CA Prostate (FDA:2010) Dosage: • 50 million CD54+ cells in 250 ml RL: infused back into the patient • 2 weekly • Cost of treatment: • $ 25,000/ vaccine Increased Overall Survival • 4.1 months (Phase III) 13
- 14. 2. (b) Vaccinationstrategies: Oncolytic Virus • CD 8+ CTL act on virus an tumor cells. All viruses have tissue-specific tropism • Influenza: Respiratory epithelium • Rabies: AchR in Nervous system • HSV-I: Skin Rationale behind oncolytic virus therapy: Once infected: Virus replicates and causes cancer cell death via: 1. Cellular lysis from viral replication 2. Hijacking the cellular death pathways 3. Promotion of cellular immunity 14
- 15. 2. (b) Oncolyticvirus therapy: Talimogene Laherparepvec (T-VEC) Genetically engineered HSV-I 1. ICP 34.5: deleted • Prevents neuronal involvement (latent infection) • Replaced with coding sequence for GM-CSF (Recruits DC, ↑ CTL response) 2. ICP 47: deleted • ↑ MHC I expression (↓ evasion by immune cells) • Promotes replication and oncolysis Advanced Melanoma: • Mutifocal, disseminated disease • In- Transit metastasis • Inoperable 15
- 16. 2. (b) Oncolyticvirus therapy: Talimogene Laherparepvec (T-VEC) Dosage and administration • Inject directly into cutaneous and subcutaneous lesions • 3 weekly for 6 months • 1 ml= 106 pfu (first dose) and 108 pfu (subsequent doses) • Clinical efficacy: • Increased survival by 23 months. • Cost: • $ 65,000 / cycle Size of lesion Dose of T-VEC <0.5 cm 0.1 ml 0.5-1.5 cm 0.5 ml 1.5-2.5 cm 1 ml 2.5-5 cm 2 ml >5 cm 4 ml 16
- 17. 3. Immune checkpointblockade: PCDP: Mechanism PD – 1 (Programmed Death receptor– 1) • Induced in response to inflammatory signals • Limits T-cell function; induces apoptosis • Cause: Prevent healthy tissue damage Ligands: PD-L1 & PD-L2 • Downregulate expression of 1. Anti-apoptotic molecules (Bcl-XL) 2. Pro-inflammatory cytokines • Also bind to CD80 (on T-Cell) 1. (-) T-Cell activation 2. (-) Cytokine production 17
- 18. 4. Immune checkpointblockade: PD1# and PD-L1# Target Drug Class Approved PD – 1 Nivolumab Human IgG4 Melanoma NSCLC RCC HD Pidilizumab Humanized IgG1 DLBCL (Ph-II) Pembrolizumab Humanized IgG4 Melanoma NSCLC HNSCC PD – L1 Atezolizumab Humanized igG1 Urothelial Cancer Lung Cancer Durvalumab Human IgG1 Urothelial Cancer 18
- 19. 4. Adoptive CellTherapy 19 CTL harvested patient Stimulated to grow and expand in vitro Transfused back into the patient Step 1: Source of CD 8+ Cytotoxic lymphocytes • Either the patients blood or tumor biopsies (AUTOLOGOUS) Step 2: Genetic Engineering via Retroviral/Lentiviral transfection of cDNA • To express a novel TCR • To express a TCR with ↑ affinity by changes in CDR Step 1: Growth of T-Cells • In medium containing IL-12, IL-15, IL-21 • Crucial for the survival and expansion of tumor specific T-cells in vitro Step 4: Myeloablative Chemo/Radiotherapy • Destroy existing Tregs that naturally suppress immune response Step 5: Re-infuse the T-cells • Specific and selective tumor destruction
- 20. 4. Adoptive CellTherapy 20 CTL harvested patient Stimulated to grow and expand in vitro Transfused back into the patient
- 21. ACT: CAR T-CellTherapy: Tisagenlecleucel Chimeric: Artificial-T cell receptors • Autologous T-Cells transfected with CD19 CAR genes • CD19 is a Pan B-Cell marker Dosing and administration • Single 50 ml i.v. infusion USFDAApproval: • Refractory/ ≥ 2 relapse B-cell ALL in patients up to 25 y.o. • Cost: • $ 475,000 21
- 22. Summary: Timeline ofCancer Immunotherapy 22
- 23. Future Prospects 1. Systemicinfusion of oncolytic viruses via PEGylation (PEGylate the virus) 2. Combination therapies 3. Improved pre-medication to reduce cytokine mediated side-effects 4. Administration of Immunotherapy as first-line therapy 5. ACT for solid tumors (Neuroblastoma, Colorectal carcinoma) in trials: currently 200 protocols with 8000 patients worldwide 23
- 24.
Editor's Notes
- #4 Rag: Recombinant Activating Gene: encode enzymes that play an important role in the rearrangement and recombination of the genes… Gamma Delta T Cell; gamma delta (γδ) T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually much less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
- #5 CTL kills the cell via Perforin-Granzyme mechanism but doesn’t damage the neighboring cells.
- #6 Central Tolerance: Occurs during thymic development of T-Cells (based on Avidity) THIS IS PERIPHERAL TOLERANCE!!! PHASE 1: ELIMINATION: Immunosurveeillance: Immunity kills via: Perforin Granzyme mechanism TRAILS (TNF related apoptosis inducing ligands) ROS PHASE 2: EQUILIBRIUM: (PHASE OF DORMANCY). Here: IMMUNOEDITING takes place as mentioned above… There is antigen and MHC loss. PHASE 3: ESCAPE: Those cells that continue to groe and expand ultimately become malignant cells.
- #10 READ IN DETAIL
- #11 READ IN DETAIL STCC: superficial transitional Cell carcinoma What is transitional epithelium? TURBT: Transurethral Resection of Bladder Tumor
- #12 Lysate: a preparation containing the products of lysis of cells.
- #13 To create the vaccine, the patient’s dendritic cells are harvested, loaded with a specific antigen ex vivo, and then introduced back into the patient to induce an immune response. More specifically, antigen-presenting cells (APCs) and other peripheral blood mononuclear cells are collected via leukapheresis from the patient’s peripheral blood and sent to a central processing facility.
- #14 Mechanism of ANTIGEN SPREADING
- #16 ICP: Infected Cell protein ICP 47: Normally reduces immune destruction of HSV-1 infected cells. The drug works by replicating in cancer cells, causing them to burst.
- #17 PFU: plaque forming unit. Number of virus particels / ml T-Vec therapy induces immune response at distant non- injected lesions also. Increased survival by 23 months.
- #20 Why Adoptive: transfer of cells into a patient. Patients blood: Leukopharesis of CD3 T-Cells.
- #21 Why Adoptive: transfer of cells into a patient. Patients blood: Leukopharesis of CD3 T-Cells.
- #22 Why Adoptive: transfer of cells into a patient.
- #24 PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as improved drug solubility, reduced dosage frequency, without diminished efficacy with potentially reduced toxicity, extended circulating life, increased drug stability, and enhanced protection from proteolytic degradation.