general oncology from devita presentation

1. Cancer Immunotherapy
Dr Om Munde

2. Therapies that enable/enhance the host immune
system to recognize and destroy cancer cells

4. Hallmarks of cancer

5. The Cancer-Immunity Cycle – Steps to generate an effective
anti-tumour response

6. Cells of the immune system
, MAIT)(ILCs)
ILCs –innate lymphoid cells
MAITs –Mucosal associated
invariant T cells
 T cells – gamma delta Tcells

7. Types of professional Antigen Presenting
Cells (APCs)

8. Activation of tumour-specific T cells by APCs
TCR with the right specificity

9. Tumor-specific and tumor-associated antigens
© QIMR Berghofer Medical Research Institute | 19
(Neoantigens)

12. • 2% of the lymphocytes circulating in the blood
called natural killer (NK) cells - already specialized to kill
certain types of target cells
specificity of the receptors with which NK cells recognize
potential targets are NOT diversified
• NK cells have
activating receptors, that activate when it binds to a
target cell, and
inhibitory receptors that transmit an inhibitory signal if
they encounter class I MHC molecules on a cell surface.
Natural Killer (NK) Cells

13. Effector responses of NK cells are regulated by inhibitory
and activatory receptors
Trends in Immunology 2011 32, 364-372DOI: (10.1016/j.it.2011.06.001)
Release of
Cytokines
Cytolysis

14. • viruses often suppress class I MHC expression in cells
they infect, the virus-infected cell becomes susceptible to
killing by NK cells.
• Because cancer cells have reduced or no class I MHC
expression, they, too, become susceptible to killing by NK
cells
• are preprogrammed to recognize their targets, they are
able to respond rapidly - innate immunity.
• secrete cytokines such as the
– anti-viral cytokine IFN-γ and the
– inflammatory cytokine TNF-α
Clinical importance

15. Antigens are macromolecules that elicit an immune response
in the body
• Antigens can be
• proteins
• polysaccharides
• conjugates of lipids with
– proteins (lipoproteins) and
– polysaccharides (glycolipids).
Antigen Presentation

16. histocompatibility molecule.
cells.
• Taken up by antigen-presenting cells (APCs):
• phagocytic cells like dendritic cells and macrophages;
• B lymphocytes ("B cells").
• Steps
• Engulf endocytosis.
• fuses with a lysosome -short peptides
• displayed at the cell surface with class II
• recognized by CD4+ T cells.
• Dendritic cells can also present intact antigen directly to B
Exogenous antigens

17. Exogenous antigens

18. • Antigens that are generated within a cell (e.g., viral proteins in
any infected cell) are degraded into fragments (e.g., peptides)
• Presented with class I histocompatibility molecule.
• recognized by CD8+ T cells Or cytotoxic T cells
Endogenous antigens

19. Endogenous antigens

20. • Are both antigen-receiving and antigen-presenting cells.
They bind intact antigens (e.g., virus particles, proteins) with
their B cell receptor (BCR).
• The B cell receptors for antigen (BCRs) are antibodies
anchored in the plasma membrane
• The affinity thousands of times higher than for
macrophage .
B lymphocytes

21. B lymphocytes

22. A CD4+ T cell recognizes the displayed antigen and is
stimulated to release lymphokines. These, in turn, stimulate
the B cell to enter the cellcycle.
• Because they stimulate B cells, these CD4+ T cells are called
Helper T cells ("Th").
• The B cell grows into a clone of cells (called plasma cells)
These synthesize receptors (BCRs) with the identical binding
site for the epitope but without the transmembrane tail.
• These antibodies are secreted into the surroundings

24. Costimulation

25. • Second signal from B cell needed to activate the T cell
• Second signal is called costimulation.
• Among the most important of these costimulators are B7
on the APC and CD28 ligand on the T cell .
• without "signal two“- causes them to self-destruct by
apoptosis.
• when body's own antigens is presented
• Fail to provide signal two or
• T cell into a regulatory T cell (Treg) that suppresses
immune responses.
Co stimulation

26. Requirements for effective priming of T cells
Front. Oncol., 10 April 2014 |https://doi.org/10.3389/fonc.2014.00077

27. Antibody mechanism of action
NK cells
FcRIIIa
-activating receptor
IgG1

28. Antibody mechanism of action
Antibody-Dependent
Cell-Mediated Cytotoxicity
Antibody-Dependent
Cellular Phagocytosis
Biolegend
Activate cellular
effector function

29. • Intrinsic
• Extrinsic tumor suppressor.
Cancer immunoediting of 3 phases /3 E s
– Elimination, or cancer immune surveillance;
– Equilibrium
– Escape, appearance of progressively growing tumors. .
Tumour suppressor mechanism

30. © QIMR Berghofer Medical Research Institute | 36
3Es
KILL BATTLE LOSE
Cancer immunoediting

31. The ability of one's own immune system to destroy cancer
cells as soon as they appear.
Cancer cells arise frequently throughout life, but the immune
system usually destroys them
For effective immune surveillance, cancer cells must express
antigens that are not found on normal cells
Immune Surveillance

32. • Mice with genes knocked out for
• Th1 cells
• cytotoxic T lymphocytes (CTLs)
• NK cells
• An increased incidence of spontaneous tumors
Are more susceptible to the induction of tumors by chemical
carcinogen
Evidence for immune surveillance

33. • Cancer patients whose tumors contain large numbers of
Tumour-infiltrating lymphocytes (TILs)
• Th1 cells and/or
• cytotoxic T lymphocytes (CTLs) and/or
• NK cells
cope with their disease better than patients with only small
numbers of these cells.
Tumour-INFILTRATING LYMPHOCYTES

34. to CD4+ Th1 cells
CD8+ cytotoxic T lymphocytes (CTLs)
• reduced efficiency of loading antigenic peptides into MHC
molecules
• reduced expression of tumor antigens
• reduced expression of
– class II MHC molecules needed to display tumor antigens
– class I MHC molecules needed to display tumor antigens to
• secretion of immunosuppressive cytokines (e.g., Transforming
Growth Factor-beta — TGF-β )
• recruitment of immunosuppressive Treg cells
Why Does Immune Surveillance Fail?

35. IMMUNE EVASION

36. CANCER VACCINES- educate T cells to better
recognise and kill the pre-existing tumor.
ADOPTIVE IMMUNOTHERAPY- activate and
increase T cell numbers to better kill tumor
IMMUNOMODULATION- use drugs or antibodies to
either
-increase immune stimulation
- overcome immune inhibition
TYPES OF IMMUNOTHERAPY

37. • Tumor cell,
• Peptide,
• Ganglioside,
• DNA,
• Viral
• Dendritic cell vaccines
Cancer Vaccines

38. Dendritic cell vaccination

39. collection of the white blood cell fraction containing
antigen-presenting cells from each patient
exposure of the cells to PAP-GM-CSF recombinant fusion
protein
• subsequent reinfusion of the cells
• Phase 3, multicenter, randomized, double-blind trial
(D9902B).
SIPULEUCEL-T

40. • Sipuleucel-T or placebo
• Median survival -25.8 months vs 21.7 months
22% reduction in mortality risk (HR, 0.78; 95% CI, 0.61–0.98; P = .03)
Only for asymptomatic or minimally symptomatic, no liver
metastases, life expectancy >6 mo, ECOG performance status
0-1

41. • Broadest spectrum of activation was elicited by GM-CSF,IL2.
• GVAX - Is a GM-CSF gene-transduced tumor vaccine.
Expression of the GM-CSF gene within either autologous or
allogeneic tumor cell populations has demonstrated evidence
of immune stimulation
• Prostate cancer and non-small-cell lung cancer.
• Results of preclinical studies justify clinical investigation
Genetically Modified Vaccines

42. • DR STEVEN ROSENBERG
first form of immune therapy to produce a high response rate
in cancer
ADOPTIVE CELL THERAPY

43. treatment of patients with cell populations that have been
expanded ex vivo is called adoptive cell transfer (ACT )
• Preparative lymphodepletion —
• using chemotherapy alone or
• in combination with total-body irradiation
this step is associated with enhanced persistence of the
transferred T cells.
ADOPTIVE CELL TRANSFER

44. Isolation of tumour-infiltrating lymphocytes and
expansion of tumour-specific T cell populations.

45. Cholangiocarcinoma
infusion enriched for TH1 CD4+ T cells that recognized a
mutated Erbb2interacting protein (ERBB2IP E805G) that
resulted in a partial response.
relapsed after 7 months, received a much more enriched
treatment (95%), and has maintained an ongoing
near-complete response for 2 years

46. • Metastatic cervical cancer was treated with CD8 TILs specific for
HPV proteins E6 and E7, which resulted in a complete response.
CD4+ cells against MAGE A3 - cervical, esophageal, and urothelial
carcinomas and osteosarcoma

47. IMMUNOMODULATORs

48. TIGIT
LANDSCAPE OF ACTIVATING AND
INHIBITORY RECEPTORS

51. CTLA-4

52. First-line Treatment For Stage IV Renal Carcinoma
Favorable-risk patients(C-2B)
Intermediate- And Poor-risk Patients(C-1)
Previously Untreated
Relapsed
Medically Unresectable
Predominantly Clear Cell

55. 29
Checkpoint blockade for cancer immunotherapy
Ribas A. N Engl J Med 2012;366:2517-2519.
e.g. ipilimumab e.g. nivolumab, pembrolizumab

56. • anti–PD-1 - Nivolumab
- Pembrolizumab
• anti–PD-L1 - Atezolizumab
- Durvalumab
- Avelumab.

60. GIT
- diarrhoea,colitis
HEPATIC
- elevated AST/ALT
ENDOCRINE
- hypophysitis
-hypothyroidism
-hyperthyroidism
COMPLICATIONS

61. CUTANEOUS
-rash, pruritis and vitiligo
RESPIRATORY
-pneumonitis, cough
GENERAL
-fatigue, nausea and vomiting
-myalgia and arthralgia.
Complications

62. ONCOLYTIC VIRUSES-Talimogene
Laherparepvec- HSV-1 (T-VEC)

63. Mediated through a combination of selective tumor cell killing
and establishment of antitumor immunity.
Immune stimulation is caused by release of cell debris and
viral antigens into the tumor microenvironment.
T-VEC : Mechanism

64. 1. Intralesional injections - unresectable stage IIIB-IV melanoma
2. Compared to GM-CSF alone
Randomized phase III trial
subcutaneous injection of GM-CSF
-improvement in response rates (26.4% vs. 5.7%, P < .001;
complete response in 11% vs. <1%)
-improvement in overall survival
OPTiM: Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec
improves durable response rate in
patients with advanced melanoma. J Clin Oncol 2015;33(25):2780–2788.

65. – TVEC plus ipilimumab VS ipilimumab alone.
-higher response rate
– Combined TVEC and pembrolizumab may enhance the
activity of each agent, as observed in a small phase II trial
where 62% of patients had objective responses.
Randomized phase II trial

66. Chimeric Antigen Receptor T-Cell Therapy
• Remarkable
success in B cell
acute leukemia
(targeting CD19);
up to 90% complete
remission
Early results in
solid tumors are
encouraging
Risk of cytokine
storm
Outgrowth of
antigen-loss
variants of tumors?
•
•
•
N Engl J Med 2014; 371:1507-1517, October 16, 2014

67. Interferons
Interleukins
• Metastatic Melanoma
• Metastatic Renal Cell Carcinoma
Largely Replaced by the Immune Check Point
inhibitors
Non-Specific Immunomodulators

68. When T-cells recognize their cognate antigen, IL-2 is
produced, resulting in autocrine and paracrine effects on the
activated T cell
NK cells and B cells express the intermediate-affinity IL-2
receptor
critical role in suppressing immune responses by CD4+CD25+
T cells /treg cells - maintain tolerance
Interleukin-2

70. • T-cell growth factor
• First true immunotherapy approved in treating cancer.
• Approved by the FDA in 1992 to treat metastatic RCC,
• also been approved in metastatic melanoma.
Side effects flu-like symptoms such as chills, fever, fatigue,
and confusion.
Interleukins -2

71. • intravenous bolus infusion of 600,000 to 720,000 IU/kg every
8 hours to tolerance using two cycles separated by
approximately 10 days (maximum of 15 doses per cycle).
• Results of this treatment are evaluated at 2 months after
first dose, and if tumor is regressing or stable, a second
course is then administered
the
• 16% objective response rate was obtained,
•
•
complete responses (6%) and
partial responses (10%).
Rosenberg et al.

72. The type I IFNs consist of at least five types- IFNa andIFNb
have been used the most clinically
• Action –
• induce the expression of (MHC) class I molecules on
tumor cells
• induce maturation of a subset of dendritic cells
• activate CTLs, NK cells, and macrophages
• cytostatic effect on tumor cells and may also promote
tumor cell apoptosis
Interferons

73. activates cell-mediated cytotoxic mechanisms that are
believed to underlie the efficacy of BCG in the prevention of
recurrence and progression
• preferred initial treatment option for CIS , high-grade Ta and
T1 disease
Bacille Calmette-Guérin

74. • Absolute
– Immunosuppressed and immunocompromised patients
Personal history of (BCG) sepsis
– Gross hematuria
– Total incontinence
• Relative
– Urinary tract infection
– Personal history of TB
Contraindications

75. • when applied as a cream, stimulates a local immune
It is used to treat very early stage skin cancers (or
pre-cancers)
The cream is applied once a day to twice a week for several
months.
Imiquimod

76. • Treatment for multiple myeloma
• By boosting the immune system
Side effects of thalidomide can include drowsiness, fatigue,
severe constipation, and neuropathy (painful nerve damage).
Lenalidomide (Revlimid®) is a newer drug that is similar to
thalidomide
Thalidomide

77. THANK YOU

83. IPILIMUMAB-fully human immunoglobulin (Ig)G1 monoclonal
antibody against CTLA-4 - response rate- 10-15%.
•
CTLA-4

84. Phase 3 double-blind, randomized, multicenter
RFS: 26.1 months VS 17.1months (IPILIMUMAB vs
PLACEBO)
High-dose ipilimumab monotherapy as an adjuvant treatment
in melanoma (C-1)
1) resected stage IIIA with metastases >1 mm
2) resected stage IIIB-C
3) resected nodal recurrence
EORTC-18071

86. • Multicenter, randomised phase 3 trial
• NIVOLUMAB vs EVEROLIMUS
• n-821
• OS- (25 VS 19.6 mon)
• ORR- (25% vs. 5%)
• PFS-(4.6 VS 4.4mon)
• ADVERSE EVENTS-(19% VS 37%)
CHECKMATE 025-ADVANCED RCC

87. • Response Rate -42% Vs 27%
• 18-month OS Rate -75 Vs 60%
• PFS -11.6mon Vs 8.4 Mon
• Multicenter, Phase IIITrial
• n-1096
IPILIMUMAB+NIVOLUMAB vs SUNITINIB
CHECKMATE- 214: Advanced RCC

88. -unresectable/metastatic melanoma

89. (KEYNOTE-021)- pembrolizumab/carboplatin/pemetrexed (C-2A)
-1st line- advanced nonsquamous NSCLC (ie, adenocarcinoma,
large cell carcinoma) or NSCLC NOS.
(KEYNOTE-024) -pembrolizumab vs platinum-based
chemotherapy.
single-agent pembrolizumab (C-1)
-first-line therapy for patients with advanced nonsquamous or
squamous NSCLC; with PD-L1 expression levels of 50% or more
(KEYNOTE-010)- pembrolizumab single agent
-subsequent therapy for patients with metastatic nonsquamous or
squamous NSCLC and PD-L1 expression levels of 1% or more

90. Nivolumab was also approved in 2014 as single-agent therapy
for the treatment of BRAF wild-type/mutation-positive,
unresectable, or metastatic melanoma
CHECKMATE-275
• multicentre, phase 2, single-arm study
• metastatic or surgically unresectable locally advanced
urothelial carcinoma
• meaningful clinical benefit, irrespective of PD-L1 expression,
• acceptable safety profile

91. .

92. Nivolumab vs docetaxel
- OS(9.2 VS 6m)
- at 18 months- OS(39% vs 23%)
-response rate-( 20% vs 9%)
NIVOLUMAB (C-1)- as subsequent therapy for patients with
metastatic nonsquamous or squamous NSCLC who have
progressed on or after first-line chemotherapy
(CheckMate-057, CheckMate-017)
CHECKMATE-017

93. DURVALUMAB(C-2A) -consolidation therapy for stage III NSCLC
who has not progressed after definite CCRT.
Phase 3 randomized trial (OAK)
Atezolizumab vs docetaxel
- metastatic NSCLC who had progressed during or after
systemic therapy
- OS-(15.6 vs. 11.2 months)

94. Eastern Cooperative Oncology Group
patients who have stage IIB andIII melanoma
• 52 weeks of high-dose IFNa-2b (HDI) versus observation
high-dose observation P
IFNa-2b (HDI)
relapse-free 1.72 years 0.98 years .0023
survival (RFS)
overall 3.82 years 2.78 years .0237
survival (OS)
• FDA approval of the HDI regimen as adjuvant therapy for
(ECOG) trial E1684

95. • randomized
• HDI vs LDI vs observation arm.
• LDI was not associated with an RFS benefit, and neither HDI
nor LDI had an impact on overall survival
Pooled meta analysis(4+8)
• 17 % reduction in recurrance
• No OS benefit
ECOG trial1690