CancerImmunotherapyAn Overview of Current Practice
WelcomeWe’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
History of Immunotherapy
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
History of ImmunotherapyNew cancer immunotherapies include multiple modalities:
Vaccines Growth factors Checkpoint inhibitors Monoclonal antibodies Cytokines Several targeted and nonspecific agents
Tumor Immunotherapy Overview
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
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
Immune SubsystemsThe 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
Innate ImmunityThe 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
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)
Inflammatory ResponseThe 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
Complement SystemThe 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)
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
Adaptive ImmunityThe 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 from ever contracting the diseaseFPO
(Adapted from Abbas, 20111)
LymphocytesLymphocytes 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
LymphocytesCytotoxic 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
(Adapted from Cheson et al, 20081)
FPO
Types of Specific Immune ResponseHumoral 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
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
Immunotherapy
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
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
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
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
T-cell Activation and Tumor SuppressionComplete 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
Brief History of Immunotherapies in
Cancer
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
Immunotherapies
Specific/Targeted ImmunotherapiesTumor-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)
Specific/Targeted ImmunotherapiesMABs 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
Antigen Non-specific ImmunotherapiesDo 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
Antigen Non-specific ImmunotherapiesThese agents include Cytokines
Five classes of cytokines are important in immunity Interleukins Interferons Tumor necrosis factors Colony-stimulating factors Chemokines
CytokinesBinding 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
Functions of Cytokines
FPO
(Adapted from Proleukin Training Module 11)
Immuno-stimulatory AgentsPotential 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
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
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
Immuno-stimulatory Agents:MABs Some commercially available MABs
Rituximab (Rituxin®) Ipilimumab (Yervoy®) Tositumomab (Bexxar®) Adalimumab (Humira®) Ibritumomab tiuxetan (Zevalin®)
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
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
Immuno-stimulatory Agents: Enzyme Inhibitors
Targeted therapies inhibit signaling enzymes, allowing tumor growth
May be called different names based on enzymes they block1FPO
1. Cancer Research UK
(Adapted from Cancer Research UK1)
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)
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
Current Immunotherapy
ApproachesHow therapies work in the body
CytokinesHeterogeneous 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)
CytokinesHuman 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)
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
Cytokines: InterferonsMechanisms 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
Cytokines: InterferonsRecombinant 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
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
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
CTLA-4 RegulationEvidence 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
PD-1/PD-L1Evidence 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
PD-1/PD-L1Anti-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
VaccinesGoal 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
VaccinesOnly 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
Other ImmunotherapiesKiller 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
1. NCI, 2014; 2. Abbas et al, 2011
(Adapted from Dendreon website3)
Other ImmunotherapiesVariation 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
Other ImmunotherapiesOther 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
Issues in Treatment with
Immunotherapy
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
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
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
Therapy Side EffectsTargeted 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
Therapy Side EffectsTargeted 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)
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
Therapy Side EffectsVaccines
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
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
Measuring Response Rates/Interpreting ResultsWHO 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
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
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
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
Challenges: Interpreting Response CriteriaWolchock 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
Challenges: Interpreting Response CriteriaEvaluating 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
Society for Immunotherapy of
Cancer (SITC) Consensus Statement
SITC GuidelinesSociety 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
SITC Guidelines: BackgroundScientific 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
SITC Guidelines: BackgroundOutlines 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
SITC Treatment RecommendationsSITC 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
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
SITC Treatment RecommendationsImmunotherapy 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
Use of Different ImmunotherapiesCytokines1
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
Use of Different ImmunotherapiesCytokines
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
Use of Different ImmunotherapiesCytokines
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
Use of Different ImmunotherapiesCytokines
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
Use of Different ImmunotherapiesCytokines
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
Use of Different ImmunotherapiesNew 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
SITC Immunotherapyby Patient Type
FPO
1. Adapted from Kaufman et al, 20131
Immunotherapeutic SequencingPanel 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
Combination TherapyCurrently 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
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
SITC Toxicity RecommendationsPanel 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
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
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
Conclusion
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
ConclusionThere 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
Questions