Therapeutic prospects in Cancer Immunotherapy. Interleukins for Renal Cell Carcinoma. BCG for Bladder Cancer. Vaccination Strategies: Oncolytic virus for melanoma, Dendritic Cell therapy for CA Prostate. Immune Checkpoint inhibitors. PD1 and PD L1 inhibitors. Adoptive Cell Therpay. CAR T Cell Therapy Clinical efficacy. Costs.

1. Therapeutic Prospects of Cancer Immunotherapy
Presenter: Dr Pranav Sopory
All India Institute of Medical Sciences
New Delhi
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2. Contents
1. Our Immune System
2. Introduction to Cancer Immunotherapy
3. Types of Immunotherapies
4. Future prospects
5. Summary
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3. Our Immune System: Classification
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4. Our Immune System
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CD 8+ 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 to mount 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
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Immunoediting leads to Tolerance

6. HELP OUR IMMUNE SYSTEM FIGHT CANCER
Aim of Cancer Immunotherapy
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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.
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8. Types of Cancer Immunotherapies
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
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9. 1. (a) Cytokine injections: 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
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10. 1. (b) BCG vaccine 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.
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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
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12. 2. (a) Vaccination strategies: 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
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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)
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14. 2. (b) Vaccination strategies: 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
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15. 2. (b) Oncolytic virus 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
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16. 2. (b) Oncolytic virus 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
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17. 3. Immune checkpoint blockade: 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 checkpoint blockade: 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
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19. 4. Adoptive Cell Therapy
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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 Cell Therapy
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CTL harvested
patient
Stimulated to
grow and
expand in vitro
Transfused back
into the patient

21. ACT: CAR T-Cell Therapy: 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
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22. Summary: Timeline of Cancer Immunotherapy
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23. Future Prospects
1. Systemic infusion 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
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24. Thank You
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