n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.

1. Cancer
Immunotherapy
An Overview of Current Practice

2. Welcome
 We’re glad you could join us
 Immunology is an exciting new frontier
 Each therapeutic agent offers a different mechanism to
boost the body’s ability to fight cancer
 The purpose of this presentation is to provide an objective
overview of the current state of cancer immunology

3. History of
Immunotherapy

4. History of Immunotherapy
 In 1796 Dr. Edward Jenner realized cowpox protected
against smallpox
 Introduced the practice of vaccination
 Immunotherapy has attracted new attention
 Multiple new oncologic agents
 Immunotherapy may soon be another agent in the standard of
care for treating cancer

5. History of Immunotherapy
 New cancer immunotherapies include multiple modalities:
 Vaccines
 Growth factors
 Checkpoint inhibitors
 Monoclonal antibodies
 Cytokines
 Several targeted and nonspecific agents

6. Tumor
Immunotherapy
Overview

7. What is the Immune System?
 A biological collection of organs, specific cells, molecules,
and other components that protect body against foreign
matter1
 Immune cells and the substances they make travel through
the body to protect it from infectious pathogens and can
also help protect against cancer cell proliferation2
1. Abbas et al, 2011; 2. Widmaier et al, 2006

8. Basis for Antimicrobial Response
 Immune system can distinguish self from non-self and
vigorously attack non-self and infected self tissues1
 Utilizes numerous mechanisms to fight disease
 Phagocytosis
 Antimicrobial peptides
 The complement system
 Adapt to and recognize specific pathogens
1. Harris et al, 2013

9. Immune Subsystems
 The human immune system can be classified into two
different subsystems
 Innate immunity (or non-specific immune system), which
reacts rapidly to any foreign substance
 Adaptive immunity (or specific immune system), which
provides a somewhat slower reaction to specific foreign
substances

10. Innate Immunity
 The innate immune system includes inherited physical and
biochemical structures present from birth that protect the
body from invading substances Innate immune defenses
are non-specific
 Respond to pathogens in a generic way
 This system does not confer long-lasting immunity against a
pathogen1
 The innate immune system is the dominant system of host
defense in most organisms2
1. Alberts et al, 2002; 2. Litman et al, 2005

11. Innate Immunity
 Innate immunity includes two
layers of protection
 External (primary) defenses
 Internal (secondary) defenses
The body’s internal
defenses activate the
internal system by
triggering the body’s
inflammatory response
FPO
(Adapted from Nutritional Oncology, 20141)

12. Inflammatory Response
 The inflammatory response activates other components of
the innate immune system’s internal defenses
 Phagocytes
 Natural killer (NK) cells
 Antimicrobial proteins
 Cytokines (e.g., histamine, prostaglandins, etc.)
 Kinins
 Chemical reactions initiated by the complement system

13. Complement System
 The complement system
 A group of 20+ proteins
 Stimulates other immune
system elements
 Can also cause lysis of bacteria
and certain other cells
 Interferons and proteins are
the two main types of non-specific
antimicrobial proteins
FPO
(Adapted from Abbas, 20111)

14. Adaptive Immunity
 Also called specific or acquired immunity
 Develops upon exposure to a pathogen or foreign substance
 Creates immunological memory
 Substances causing this response are antigens
 The immune response can destroy anything containing the
antigen, whether bacteria or cancer cells
 Adaptive immunity is highly specific to its molecular
structural characteristics
 This leads to an enhanced immune response to subsequent
encounters with that same pathogen1
1. Abbas et al, 2011

15. Adaptive Immunity
The process of adaptive or acquired
immunity is the basis of vaccines
By exposing the immune system to
an inactivated form of a pathogen,
vaccination protects the person
FPO from ever contracting the disease
(Adapted from Abbas, 20111)

16. Lymphocytes
 Lymphocytes are involved in adaptive immunity
 There are various classes of lymphocytes
 B lymphocytes recognize soluble antigens and develop into
antibody-secreting cells
 Helper T lymphocytes recognize antigens on the surfaces of
antigen-presenting cells(APCs) and secrete cytokines
 Cytokines stimulate different mechanisms of immunity and
inflammation

17. Lymphocytes
 Cytotoxic T lymphocytes
recognize antigens on infected
cells and kill these cells
 Regulatory T cells suppress
and prevent immune
response (e.g., to self
antigens)
 NK cells use receptors with
more limited diversity than T
or B cell antigen receptors
FPO
(Adapted from Cheson et al, 20081)

18. Types of Specific Immune Response
Humoral Immunity
 Mediated by proteins, including
antibodies, in the blood and
other bodily fluids
 Produces a cascade of chemicals
from the complement system
 Antibodies are produced by
plasma cells (derived from B cells)
 Bind to specific antigens,
inactivating them and/or
marking them for destruction
Cellular Immunity
 Also called cell-mediated immunity
 Mediated by T cells
 May attack target cells directly or
indirectly by activating other
immune cells
 Enhances the inflammatory
response
 Cellular immunity primarily targets
antigenic molecules and
microorganisms

19. Immune System Disorders
 Includes autoimmune diseases, immunodeficiency inflammatory
diseases and cancer1,2
 Immunodeficiency may be due to an immune system that is less
active than normal
 Recurring and life-threatening infections
 Result of genetic conditions, acquired disease(HIV), or the use of
immunosuppressive medication1
 Autoimmunity
 Results from a hyperactive immune system
 Attacks body’s innate tissue as a foreign pathogen
 Common autoimmune diseases include Hashimoto's thyroiditis,
rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus
erythematosus
1. Coussens et al, 2001; 2. O’Byrne et al, 2001

20. Immunotherapy

21. What is immunotherapy?
 The NCI defines immunotherapy as “treatment to boost or
restore the ability of the immune system to fight cancer,
infections, and other diseases”1
 Tumor immunotherapy Aims to augment the weak host
immune response (active immunity)
 Or to administer tumor-specific antibodies or T cells, a form of
passive immunity2
1. National Cancer Institute, 2014; 2. Abbas et al, 2011

22. How Does it Work?
 Immunotherapy does not work in one specific mechanism
of action
 However, all immunotherapy modalities are intended to
augment or restore the body’s own immune function by
some means1
 May be quite different from the traditional cancer
treatments of chemotherapy/targeted therapy, radiation,
and surgery, which intend to act directly upon the targeted
tumor
1. Mellman et al, 2011

23. Treatment Approaches
 In immunotherapy, each modality may encompass several
different treatment approaches—or some combination of:
 Therapeutic cancer vaccines
 Cytokines
 Immunological checkpoint inhibitors
 Targeted monoclonal antibodies

24. T-cell Activation and Tumor
Suppression
 Antigen-presenting cells (APCs) take up foreign antigens,
are processed by the APC and then bound to major
histocompatibility complex (MHC) molecules on the APC
surface
 MHC molecules present the processed antigen to T cells
 T cells interact with the complex formed by antigen bound
to MHC molecule, producing a
T-cell activation signal known as signal 11
1. Bowes et al, 2014

25. T-cell Activation and Tumor
Suppression
 Complete activation requires a second APC signal, known
as signal 2
 Once activated, T cells can directly kill tumor cells that
express the antigen for which it has specificity
 Activated T cells can release cytokines that kill tumor cells
or chemicals that attract other immune cells (e.g.,
macrophages), to destroy tumor cells1
1. Bowes et al, 2014

26. Brief History of
Immunotherapies in
Cancer

27. Past Century
 Stages of cancer immunotherapy development1
 1890 – Cancer vaccine developed; demonstrated patient
benefit
 1960’s – Tumor-specific monoclonal antibodies released
 1970’s/1980’s – Clinical benefit of cancer immunotherapy
does not fulfill expectations
 Late 1990’s – Several cancer immunotherapy drugs spur
renaissance of interest
1. Kirkwood et al, 2012

28. Immunotherapies

29. Specific/Targeted Immunotherapies
 Tumor-specific monoclonal
antibodies (MABs) act via direct or
indirect immune response resulting
in cell death
 MABs are produced from single B cell
clone and consist of multiple identical
copies
 MABs have several
clinical/therapeutic uses
 Clinical testing/research
 Immunotherapy against specific
cancers
FPO
(Adapted from Halim, 20001)

30. Specific/Targeted
Immunotherapies
 MABs work through various mechanisms of action to elicit cell death1
 Blocking signaling pathways necessary for tumor growth
 Triggers immune-mediated cytotoxic response
 Blocking angiogenesis1,2,3
1. Kirkwood et al, 2012; 2. Cheson et al, 2008; 3. Weiner et al, 2010; 4. Halim, 2000

31. Antigen Non-specific
Immunotherapies
 Do not target cancer cells specifically
 Stimulate the immune system in a more general way that
may lead to a better immune response against cancer cells
 Non-specific cancer immunotherapies may be
administered as:
 Monotherapy
 Adjuvant therapy to boost the immune system and potentiate
other agents, such as vaccines

32. Antigen Non-specific
Immunotherapies
 These agents include Cytokines
 Five classes of cytokines are important in immunity
 Interleukins
 Interferons
 Tumor necrosis factors
 Colony-stimulating factors
 Chemokines

33. Cytokines
 Binding of a cytokine to a cell can have a variety of
different effects
 Inducing production of more cytokine molecules
 Promoting or inhibiting cytokine activity
 Activating or suppressing target cell activity, proliferation, or
differentiation
 Cytokines as Cancer Immunotherapy
 Recombinant versions of some cytokines are produced
commercially for cancer and other disorders
 Interleukins, interferons, and colony-stimulating factors

34. Functions of Cytokines
FPO
(Adapted from Proleukin Training Module 11)

35. Immuno-stimulatory Agents
 Potential mechanisms of these therapies vary
 Direct anti-tumor effects
 Reversal of immune suppression
 Activation of innate immunity
 Antigen-non-specific T cell activation1
1. Monjazeb et al, 2012

36. Immuno-stimulatory Agents
 CpG oligonucleotides
 Potent stimulators of both innate and adaptive immune systems
 Currently being examined for cancer immunotherapy1
 Bacillus Calmette-Guérin (BCG)
 Nonspecific immune stimulation
 Activates macrophages and promotes macrophage-mediated killing
of tumor cells
 Used as adjuvant may stimulate T cell responses
 BCG is currently used to treat bladder cancer2
1. Bodera et al, 2012; 2. Abbas et al, 2011

37. Immuno-stimulatory Agents:
MABs
 Antibodies targeted against receptors (MABs)
 100+ trials with therapeutic cancer agents1
 Used to treat rheumatoid arthritis,2 multiple sclerosis,3 and many
forms of cancer
 Mainstay in treating breast cancer, non-Hodgkin's lymphoma,4 colorectal
cancer, leukemia, and head and neck cancers
 Demonstrated improved Overall Survival and Progression Free
Survival in randomized, Phase 3 clinical trials5,6,
 Response rates (RR) 8-10% when used as monotherapy in advanced
stage, heavily pretreated, and recurrent disease
 RR increased to 30% combined with chemotherapy and/or radiotherapy7
1. Abbas et al, 2011; 2. Feldman et al, 2001; 3. Doggrell, 2003; 4. Vogel et al, 2001; 5. Cheson et al, 2008; 6. Slamon et al,
2001; 7. Robak et al, 2010; 8. Kirkwood et al, 2012

38. Immuno-stimulatory Agents:
MABs
 Some commercially available MABs
 Rituximab (Rituxin®)
 Ipilimumab (Yervoy®)
 Tositumomab (Bexxar®)
 Adalimumab (Humira®)
 Ibritumomab tiuxetan (Zevalin®)

39. Immuno-stimulatory Agents
 Agonistic CD40
 CD40 is a tumor necrosis factor receptor expressed on APCs
such as:
 Dendritic cells (DC)
 B cells
 Monocytes
 Many non-immune cells
 A wide range of tumors
 Agents currently in research
 May be combined with vaccines and chemotherapy in the
future

40. Immuno-stimulatory Agents
 Inhibitory CTLA-4 antibodies
 CTLA-4 is a protein found on the surface of T cells
 Normally acts as a type of “off switch” to keep T cells from
attacking body’s other cells
 CTLA-4 can also stop T cells from attacking tumors
 Ipilimumab (Yervoy®) is a MAB that attaches to CTLA-4 and
stops T cell inhibition
 This boosts the immune response

41. Immuno-stimulatory Agents: Enzyme
Inhibitors
 Targeted therapies inhibit
signaling enzymes, allowing
tumor growth
 May be called different names
FPO based on enzymes they block1
(Adapted from Cancer Research UK1)
1. Cancer Research UK

42. Immuno-stimulatory Agents: Enzyme
Inhibitors
 Tyrosine kinase inhibitors
(TKIs) include:
 Axitinib (Inlyta®)
 Dasatinib (Sprycel®)
 Erlotinib (Tarceva®)
 Gefitinib (Iressa®)
 Imatinib (Glivec®)
 Pazopanib (Votrient®)
 Sorafenib (Nexavar®)
 Sunitinib (Sutent®)
FPO
(Adapted from Cancer Research UK1)

44. Immuno-stimulatory Agents
 Proteosome inhibitors
 Proteasomes are found in all cells
 Help degrade excess protein
 Proteasome inhibitors cause a build-up of unwanted
proteins in the cell Makes cancer cells die Bortezomib
(Velcade®) is a proteasome inhibitor used to treat
multiple myeloma1
 Signal-transduction inhibitors and multi-targeted kinase
inhibitors

46. Current
Immunotherapy
Approaches
How therapies work in the body

47. Cytokines
 Heterogeneous group of
secreted proteins produced by
multiple cells
 Mediates and regulates all
aspects of innate and adaptive
immunity
FPO
(Adapted from Proleukin Training Module 11)

48. Cytokines
 Human genome contains ~180
genes that may encode
proteins with structural
cytokine characteristics1
 Recombinant cytokines
produced commercially for
use in cancer and other
disorders
FPO
(Adapted from Proleukin Training Module 12)

49. Cytokines: Interferons
 Interferon alpha-2b (Intron-A®), Interferon alpha-2ba
(Roferon-A®) and Pegylated Interferon family of proteins
 Biologic response modifier1 that activates macrophages and
NK cells
 Stimulate cellular responses that protect against viruses

50. Cytokines: Interferons
 Mechanisms of the antineoplastic effects of
IFN-α probably include:
 Inhibition of tumor cell proliferation
 Increased cytotoxic activity of NK cells
 Increased class I MHC expression on tumor cells
 Makes them more susceptible to killing by CTLs
 Shown to have direct effects on tumor cells1
 Anti-proliferative
 Pro-apoptotic
 Anti-angiogenic

51. Cytokines: Interferons
 Recombinant IFNα used in treatment of some cancers
 Approved for use in1,2:
 Hairy cell leukemia
 Malignant melanoma
 AIDS-related Kaposi's sarcoma
 Follicular non-Hodgkin's lymphoma

52. Cytokines: Interleukins
 Interleukins produced primarily
by T cells and macrophages
 Most extensive clinical
experience with cytokines is
high-dose Interleukin-2 (IL-2 or
Proleukin®)2
FPO
(Adapted from Mayer, 20101)
1. Meyer, 2010; 2. Abbas et al, 2011

53. Cytokines: Interleukins
 IL-2 plays key role in activation,
maturation, and/or growth of many
immune cells
 Stimulates production by T cells of TNF
and IFN-γ2
 CD4 cells (helper T cells)
 CD8 cells (cytotoxic T cells)
 B cells, NK cells, and macrophages
 IL-7, IL-12, and IL-21 also being
studied as oncological adjuvants and
monotherapy
FPO
(Adapted from Mayer, 20101)
1. Meyer, 2010; 2. Abbas et al, 2011

55. CTLA-4 Regulation
 Evidence shows that T cell responses to some tumors are inhibited by
involvement of cytotoxic T lymphocyte-associated antigen (CTLA-4)1
 CTLA-4 is a negative regulator of T cell activation2
 Ipilimumab (Yervoy®)is a fully human anti CTLA-4 agent
 Binds to CTLA-4 and blocks interaction of CTLA-4 with its ligands,
CD80/CD86
 Blockade of CTLA-4 has shown to augment T-cell activation and
proliferation
 Indicated for the treatment of metastatic or unresectable melanoma
 The mechanism of action in melanoma is indirect, possibly through T-cell
mediated anti-tumor immune responses2
1. Abbas et al, 2011; 2. Yervoy® PI, 2013

56. PD-1/PD-L1
 Evidence shows that T cell response in some tumors is inhibited by
the programmed cell death protein 1 (PD-1/PD-L1) pathway
 PD-1 keeps immune response in check
 Antibody blockade of PD-1 is effective in enhancing
T cell killing of tumors in mice and human clinical trials1
 Compared to CTLA-4, seems to be found more often in
T cells in tumors
 Attaches to PD-L1, a protein found on some normal and cancer cells
 When PD-1 binds to PD-L1, directs T cell to not attack tumor
 Some cancer cells have large amounts of PD-L1 on cell surface
1. Abbas et al, 2011

57. PD-1/PD-L1
 Anti-PD-1 antibody MK-3475 (formerly lambrolizumab) being
studied in:
 Metastatic melanoma
 Thirteen clinical trials with 30+ tumor types1
 BMS-936558 (nivolumab), showed promising Phase II results in:
 Non-small cell lung cancer
 Renal carcinoma Colorectal cancer
 Many patients don't respond, but ones that do seem to show
benefit2
1. Roth, 2014; 2. Topalian et al, 2012

58. Vaccines
 Goal of cancer vaccine therapy is to treat disease by
promoting intense, cancer-specific,
T cell immune response
 Vaccines derived from autologous or allogeneic tissue
 Autologous vaccines use tumor cells from patient receiving
vaccine
 Contains all tumor antigens present in tumor, and is MHC-matched
with the patient
 Allogeneic vaccines prepared with tumor cells from others
 Easier to manufacture in quantity, but may lack unique
patient antigens

59. Vaccines
 Only cancer treatment vaccine approved by FDA thus far:
 Sipuleucel-T (Provenge®)
 An autologous vaccine approved for metastatic prostate
cancer
 Development of virally induced tumors can be blocked by
preventive vaccination with viral antigens or attenuated
live viruses
 HPV vaccines promise to reduce the incidence of HPV-induced
tumors1
1. Abbas et al, 2011

60. Other Immunotherapies
 Killer T cell and regulatory T cell
manipulation Lymphokine-activated
killer cell (LAK cell) is a
white blood cell stimulated to kill
tumor cells1
 Adoptive therapy with autologous
LAK cells and in vivo administration
of IL-2 or chemotherapeutic drugs
has yielded results in mice, with
regression of solid tumors2
FPO
(Adapted from Dendreon website3)
1. NCI, 2014; 2. Abbas et al, 2011

61. Other Immunotherapies
 Variation of adoptive therapy isolates tumor-infiltrating
lymphocytes (TILs ) from inflammatory infiltrate in and
around solid tumors
 TILs are obtained from surgical resection specimens and
expanded by culture in IL-2
 TILs may be enriched for tumor-specific cytotoxic
T lymphocytes (CTLs) and for activated NK cells
 TIL therapy for metastatic melanoma being used in various
cancer centers1
1. Abbas et al, 2011

62. Other Immunotherapies
 Other drugs boost immune system in a non-specific way, similar
to cytokines
 Unlike cytokines, these therapies are not naturally found in the
body
 Used to treat multiple myeloma and some other cancers
 Known as immunomodulating drugs (IMiDs), and include:
 Thalidomide (Thalomid®)
 Lenalidomide (Revlimid®)
 Pomalidomide (Pomalyst®)
 Thought to work by boosting immune system
 Not exactly clear how

63. Issues in Treatment
with
Immunotherapy

64. Therapy Side Effects
 Interferon-alpha side effects can include:
 Flu-like symptoms (chills, fever, headache, fatigue, loss of appetite,
nausea, vomiting)
 Low white blood cell counts (which increase the risk of infection)
 Skin rashes
 Thinning hair
 Side effects can be severe and make treatment difficult to tolerate
 Depression can also be of concern
 Most side effects do not continue after treatment discontinuation,
but fatigue can last longer
 Other rare long-term effects include nerve damage1
1. INTRON® A PI, 2014

65. Therapy Side Effects
 IL-2
 Acute side effects of IL-2 can be severe but predictable:
 Flu-like symptoms such as chills, fever, fatigue, and
confusion
 Patients may experience nausea, vomiting, or diarrhea
 Many people develop low blood pressure due to capillary
leak syndrome, which must be treated with pressor support
 Rare but potentially serious side effects include an abnormal
heartbeat, chest pain, and other heart problems, and
impaired neutrophil function1
1. PROLEUKIN® PI, 2012

66. Therapy Side Effects
 IL-2 (cont’d)
 Because of the possible side effects, when IL-2 is given in high
doses, it must be done in a hospital by an experienced staff
 IL-2 has adverse events noted in the PI and evidenced by its
Black Box Warning
 Toxicity management and proper patient selection is necessary
 Toxicities are rarely chronic
 According to Atkins et al, “Patients experienced significant
treatment-related morbidity, but long-term sequelae for
patients receiving high-dose IL-2 have been extremely rare”1
1. Atkins et al, 2000

67. Therapy Side Effects
 Targeted Therapies
 Common skin toxicity of sorafenib (also sunitinib) is hand–foot skin
reaction, commonly accompanied by paraesthesias1
 Other skin toxicities of TKIs include rash, stomatitis, alopecia,
pruritus, and subungual splinter hemorrhages2
 In a 106-patient phase II study of sunitinib as second-line therapy of
advanced renal cell cancer, the most common adverse events were
fatigue(28%), diarrhea(20%), anemia (26%, and neutropenia(42%)3
1. Widakowich et al, 2007; 2. Robert et al, 2005; Motzer et al, 2006

68. Therapy Side Effects
 Targeted Therapies
“It is important to analyze the biologic effects of targeted therapy
in cancer cells as well as in normal tissues. Many of the adverse
events related to these agents have been described only after
more prolonged use, such as the case of cardiac toxicity due to
trastuzumab or ILD reported with gefitinib. Some of these effects
were unpredictable and not observed during the early phases of
drug development.”
(Widakowich et al, 20071)

69. Therapy Side Effects
 Ipilibumab
 Can allow immune system to attack some normal organs,
leading to serious side effects in some patients
 Most common side effects include fatigue, diarrhea, skin rash,
and itching Less often, can cause more serious GI issues, or
problems with nerves, skin, eyes, or other organs
 In some people these side effects have been fatal1
1. YERVOY® PI, 2013

70. Therapy Side Effects
 Vaccines
 PROVENGE® (sipuleucel-T)
 Side effects are generally mild to moderate and most last
only a day or two
 In clinical trials, only 1.5% of men discontinued their
treatment because of side effects
 The most common side effects include chills, fatigue, fever,
and back pain
 In clinical studies, some men experienced more serious side
effects, such as chest pain, irregular heartbeat, nausea, and
vomiting1
1. PROVENGE® PI, 2011

72. Measuring Response
Rates/Interpreting Results
 Commonly used criteria include World Health Organization
(WHO), Response Evaluation Criteria in Solid Tumors
(RECIST), and the revised RECIST 1.1.31
 Initial guidelines were primarily designed for patients
receiving chemotherapy
 More recently, new measures have been developed
specifically for patients who are receiving immune-based
therapies1
1. Bowes, 2014

73. Measuring Response
Rates/Interpreting Results
 WHO criteria
 Complete response (CR) – disappearance of all lesions
 Partial response (PR) – tumor burden, measured using the SPD
for all baseline lesions, decreased by ≥50%
 Progressive disease (PD) – an increase in tumor burden by
≥25% from baseline
 Stable disease – smaller changes in tumor burden that did not
meet the criteria for PD, PR, or CR
 Earlier immunotherapies, such as interferon and IL-2, used the
more stringent criteria of a decrease of ≥50% to be considered
a PR1
1. Bowes, 2014

74. Measuring Response
Rates/Interpreting Results
 RECIST criteria were designed to evaluate response to traditional
chemotherapies with a cytotoxic MOA and thus do not clearly assess
the efficacy of immunotherapy, which works differently1,2
 In initial RECIST guidelines (Version 1.0)
 CR defined as the disappearance of all target lesions
 PR ≥ 30% decrease in the sum of the longest diameters of target lesions
 PD was ≥ 20% increase in the sum of the longest diameter of target
lesions, or the appearance of one or more new lesions
 SD was neither PR or PD3
 More recently reviewed immunotherapies were often evaluated for
response using the RECIST criteria
1. Sharma et al, 2011; Kirkwood et al, 2012; Nishino et al, 2010

75. Challenges: Interpreting Response
Criteria
 The importance of SD in immunotherapy
 Immune-modifying agents require more time than
chemotherapy to induce an antitumor response
 Tumor volume may even increase during the early phases of
treatment
 Use of immune-related response criteria for cancer
patients has been shown to identify a substantial number
of patients who are responding to immune-based
treatments
 Would have been considered to have failed treatment using
conventional response criteria1
1. Bowes, 2014

76. Challenges: Interpreting Response
Criteria
 Immunotherapies present potential challenges to
assessment of treatment using conventional response
criteria
 Potential limitation of some immune-based treatment
 May take relatively long period to mount effective immune
response
 Patient or the treating physician may conclude treatment
is not effective before immune system has enough time to
fully respond to therapy1
1. Bowes, 2014

77. Challenges: Interpreting
Response Criteria
 Wolchock et al proposed alternative response
criteria for immunotherapy1
 Criteria referred to as “immune-related
response criteria”2
 Define response patterns observed in
immunotherapy, and identify successful
outcomes
 Originally for metastatic melanoma
 Recent studies and reviews also proposed
application in:
 RCC, NSCL, and prostate cancer
1. Bowes, 2014; 2. Chen, 2013

78. Challenges: Interpreting
Response Criteria
 Evaluating immunology trials and response
patterns, only 2/4 patterns would be classified as
“treatment responses” using RECIST or WHO
criteria
 Other 2 classified as treatment failures even though
patients eventually responded1
 Important that radiologists have thorough
understanding of immune-modifying strategies
shown to improve outcomes in cancer patients
1. Bowes, 2014

79. Society for
Immunotherapy of
Cancer (SITC)
Consensus
Statement

80. SITC Guidelines
 Society for Immunotherapy of Cancer (SITC) Consensus
Statement on Tumor Immunotherapy for the Treatment of
Cutaneous Melanoma1
 Published August 2013
 First evidence-based recommendations for when and
how to implement melanoma therapies
 Provides consensus recommendations from 30
melanoma experts for the use of immunotherapy in the
treatment of melanoma
 Before the consensus statement, lack of evidence-based
guidelines created obstacles and discord in oncology
1. Kaufman et al, 2013

81. SITC Guidelines: Background
 Scientific literature search identified a 986-item
bibliography1
 Data ensured recommendations were evidence-based
 From peer-reviewed literature and clinical
experience, panel put forth recommendations
1. Kaufman et al, 2013

82. SITC Guidelines: Background
 Outlines role of immunotherapy in management
of Stage IV melanoma1
 Interleukin-2 (IL-2, PROLEUKIN®), and ipilimumab
(YERVOY®) monotherapy
 The above in combination with FDA-approved
agents
 Dacarbazine
 BRAF inhibitor Vemurafenib (ZELBORAF®)
1. Kaufman et al, 2013

83. SITC Treatment
Recommendations
 SITC reviewed patient selection, toxicities, clinical
end points, and sequencing/combination
therapy
 The panel recognizes several systemic treatment
options for unresectable stage IV melanoma1
 High-dose IL-2
 Ipilimumab
 Vemurafenib
 Dabrafenib
 Trametinib for patients with BRAF mutated tumors
 Clinical trials
 Cytotoxic chemotherapy
1. Kaufman et al, 2013

84. SITC Treatment
Recommendations
 In Stage IV melanoma panel recommended
 IL-2 1
 Considered first line
 Patients with good PS
 Meet local institutional guidelines for IL-2 administration
 Patients who are not candidates for IL-2 therapy should
consider ipilimumab
 BRAF inhibitor for patients with BRAF-mutated melanoma2
who:
 Have poor performance status (PS)
 Have untreated CNS disease
 Are not candidates for clinical trial
1. Kaufman et al, 2013; 2. ibid

85. SITC Treatment
Recommendations
 Immunotherapy considered for patients
treated with a BRAF inhibitor if:
 PS improved with treatment
 CNS disease is controlled
 IL-2 considered for patients with good PS
 Ipilimumab considered for patients with poor PS who
respond to a BRAF inhibitor and are not candidates
for IL-2 treatment or clinical trials1
1. Kaufman et al, 2013

86. Use of Different
Immunotherapies
 Cytokines1
 Data supporting high-dose IL-2, ipilimumab and
targeted therapy in the treatment of patients with
stage IV melanoma
 Interferons
 SITC guidelines do not recommend interferon-alpha
for stage IV metastatic melanoma
1. Kaufman et al, 2013

87. Use of Different
Immunotherapies
 Cytokines
 Interleukin-21
 Early clinical trials of high-dose IL-2
 Objective response rates of 16–17%
 6–7% complete response rate
 Further follow-up shows 80–90% of complete
responders alive 10–15 years later
 Durability and consistency of responses led to FDA
approval of IL-2 for metastatic melanoma in 1998
1. Kaufman et al, 2013

88. Use of Different
Immunotherapies
 Cytokines
 Ipilimumab1
 Evaluated in several phase I and II clinical trials
 Demonstrated an improvement in overall survival
in patients with metastatic melanoma in two large
trials
 In one study, patients with metastatic melanoma
receiving ipilimumab had an improvement in
overall survival versus vaccine alone
 Ipilimumab+dacarbazine versus dacarbazine
alone showed an increase in overall survival
1. Kaufman et al, 2013

89. Use of Different
Immunotherapies
 Cytokines
 Conventional chemotherapy produces direct cell-killing
toxicity that results in decreased tumor size
often observed after 2 cycles (6-8 weeks)
 In one study, patients treated with ipilimumab did
not begin to exhibit significant slowing of disease
progression until after 12 weeks1
 In some cases, patients first exhibited increase in
tumor volume, followed by clearing of tumor
several months later
 All panelists agree laboratory reports should be
obtained before each ipilimumab infusion
 Panel was divided on long-term follow-up, with
some members recommending repeat laboratory
analysis every 3 months for 2 years
1. Kaufman et al, 2013

90. Use of Different
Immunotherapies
 Cytokines
 BRAF inhibitor vemurafenib1
 Evaluated in 675 previously untreated metastatic
melanoma patients with the BRAF mutation
 Patients received either vemurafenib or
dacarbazine
 A significant improvement in overall survival and
progression-free survival was observed for those
receiving vemurafenib
1. Kaufman et al, 2013

91. Use of Different
Immunotherapies
 New therapies1
 Success of immunotherapy in treatment of
melanoma expected to result in approval and
development of additional agents over next several
years
 Programmed death 1 (PD-1) T-cell checkpoint
inhibitors for cancer therapy
 Both PD-1 and PD-L1 seem promising for cancer
immunotherapy
1. Kaufman et al, 2013

92. SITC Immunotherapy
by Patient Type
FPO
1. Adapted from Kaufman et al, 20131

93. Immunotherapeutic
Sequencing
 Panel recognized1:
 Limited to no data on drug sequencing
 IL-2 should not be used in patients with poor or
declining PS
 There are no safety data with IL-2 after ipilimumab or
with vemurafenib
 Panel recommended IL-2 be given as first-line
therapy in suitable patients
1. Kaufman et al, 2013

94. Combination Therapy
 Currently no prospective data from well
controlled trials on clinical outcomes with
concurrent immunotherapy
 Several reports of potent abscopal effect when
ipilimumab and IL-2 used after localized
radiotherapy1
 Suggests that this immunotherapy combination and
radiation treatment might be a possible therapeutic
strategy
1. Kaufman et al, 2013

95. SITC Toxicity
Recommendations
 Immunotherapy associated with a range of
toxicities
 Need to carefully monitor during and after
treatment
 Autoimmune-like symptoms particularly important
 Reported with interferon-α2b, IL-2, and ipilimumab

96. SITC Toxicity
Recommendations
 Panel recommends for all patients receiving
immunotherapy1:
 Routine thyroid function studies
 Complete blood counts
 Liver function and metabolic panels
 Serum LDH tests
 Baseline
 Weekly during induction
 Monthly if on standard high-dose interferon-α2b
therapy
1. Kaufman et al, 2013

97. SITC Toxicity
Recommendations
 Interferon-related depression
 Depression and related constitutional symptoms can
be major challenge during interferon-α2b therapy
 Panel recommends significant history of depression
be contraindication to any form of interferon
treatment
 Selective use of antidepressants in patients who
develop depressive symptoms during treatment

98. SITC Toxicity
Recommendations
 Ipilimumab side effects
 Asymptomatic vitiligo
 Autoimmune thyroiditis
 Symptomatic skin, gastrointestinal, hepatic and
endocrine immune-related toxic effects
 IL-2
 May be beneficial to get daily labs during IL-2
treatment

99. Conclusion

100. Conclusion
 Immunotherapy is an established modality for
treating patients with melanoma where some
patients achieve durable therapeutic response1
 Key points include
 Evaluation of therapy
 Differences between response in treating with
chemotherapies vs. immunotherapies
 Side effect management

101. Conclusion
 There are exciting new horizons with ongoing
research in
 Drug sequencing
 New products
 Combination therapies
 With the approval of multiple oncologic agents,
immunotherapy will soon join the traditional
therapies of chemotherapy, surgery, and
radiation therapy as the standard of care in the
treatment of cancer

102. Questions