Download Biomarkers 2015 - Kentucky Cancer Registry

The Emerging Role of
Immunotherapy in Cancer
Care 2015
Renato V. La Rocca, MD, FACP
Norton Cancer Institute
Louisville, Kentucky
Renato V. La Rocca, MD,
FACP
I have no conflicts to disclose with
respect to this presentation
The Emerging Role of Immunotherapy in
Cancer Care 2015
Learning Objectives:
1. Discuss the emerging role of immunotherapy in
cancer care
2. Describe two new targeted therapies for cancer
approved in the last 24 months
3. Define the terms prognostic marker and predictive
marker
Improved Survival Remains a
Challenge
in Some Advanced Cancers
5-year Survival in Advanced Cancers (%)1
•
•
5-year survival remains poor for
many patients with advanced
metastatic solid tumors1
In the United States, it is estimated
that2:
•
A total of 589,430 deaths due to
cancer will occur in 2015
Colorectal
Lung
4.0
12.9
Kidney and
Renal Pelvis
12.1
Bladder
Melanoma
16.1
5.5
There is an ongoing need for new treatments and therapeutic
modalities for patients with advanced cancers3
1. Surveillance, Epidemiology and End Results (SEER) Program. Available at: http://seer.cancer.gov. Accessed March 26, 2015.
2. Siegel RL et al. CA Cancer J Clin. 2015;65(1):5-29.
3. Rosenberg SA. Sci Transl Med. 2012;4(127ps8):1-5.
Hallmarks of cancer
As normal cells progressively evolve to a neoplastic state, they can acquire a succession
of hallmark capabilities1:
Activating
invasion and
metastasis
Sustaining
proliferative
signaling
Evading
growth
suppressors
Resisting
cell death
8 hallmarks
of cancer1
Avoiding
immune
destruction*
Inducing
angiogenesis
Enabling
replicative
immortality
For Immuno-Oncology
therapies (I-O therapies)
to work, they generally
incorporate an
understanding of the
mechanisms of tumor
escape.2,3
I-O therapies seek to
modulate the immune
system to promote
antitumor activity, and
counteract this hallmark.4
Deregulating
cellular
energetics*
*Emerging
hallmarks
5
1. Hanahan D, Weinberg RA. Cell. 2011; 144(5) 646-674. 2. Pardoll DM. Nat Rev Cancer. 2012;12:252-264
3. Kirkwood JM, et al. CA Cancer J Clin. 2012; 62:309-335
4. Mellman I, et al. Nature. 2011;480:480-489
Immuno oncology Is an Evolving
Cancer Treatment Modality
Immuno oncology is a fundamentally different approach to fighting cancer that
harnesses the body’s own immune system1
Chemotherapy/
Targeted therapy
Surgery
Radiation
Immuno-Oncology
Through I-O research, therapies are being investigated in an attempt to utilize the
body's own immune system to fight cancer1-3
1. Murphy JF. Oncology. 2010;4:67-80.
2. Kirkwood JM et al. CA Cancer J Clin. 2012;62(5):309-335.
3. Borghaei H et al. Eur J Pharmacol. 2009;625(1-3):41-54.
Components of the
immune system
Tumorassociated
antigens
• are abnormal cell
substances/proteins
(tumor antigens) which
can be recognized and
responded to by the
immune system1
Antigen-presenting
cells
T cells
1
• take up antigens from
infected or malignant cells
and processes them into
shorter peptide segments2
• have T-cell receptors,
which can recognize
tumor-associated
antigens
• present antigen to T cells to
mobilize an immune
response2
• play a major role in
killing infected or
malignant cells when
activated
• help perpetuate ongoing
immune responses
1. Pardoll DM. Nat Rev Cancer. 2012;12:252-264 2. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science;
2004
Components of the
immune system
B cells
Antibodies
NK cells
• display B-cell receptors,
which can bind free
floating antigens in the
blood or lymph
• are secreted by activated
B cells, called plasma
cells1
• can recognize infected
or malignant cells
innately without contact
with an antigenpresenting cell or
antibody (this allows
NK cells to launch
rapid responses against
stressed cells)
1
• once activated, B cells
differentiate to become
plasma cells which can
secrete large quantities
of antibodies against a
specific antigen1
• tag antigen-containing
cells for attack by other
parts of the immune
system, or neutralize
their targets directly by
blocking important
mechanisms1
1
• can also attack based on
recognition of
antibodies on a cell
surface
1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004
• Under normal conditions, there are a number of immune activation and inhibition
pathways that modulate the immune response and protect healthy tissues from
collateral damage during an immune response.1,7
• Tumor evasion of the immune system may be associated with an imbalance in immune
activation and inhibition.1-5
Tumors may down-regulate
co-stimulatory pathways.2-3
Co-stimulatory receptors include:
Tumors may up-regulate immune
checkpoints (inhibitory signaling
pathways).2,3,5,6 Checkpoint pathway
molecules include:
•
•
•
•
•
•
•
•
CD28
CD40
OX40
CD137
IMMUNE SYSTEM PATHWAYS
Immune system pathways
LAG-3
CTLA-4
B7-H3
PD-1
1. Baruah P, et al. Immunobiology. 2012;217(7):669-675 2. Hemon P, et al. J Immunol. 2011,186:5173-5183 3. Pardoll DM. Nat Rev Cancer. 2012;12:252-264 4. Kirkwood JM, et al. CA
Cancer J Clin. 2012;62:309-335 5. Zang X, et al. PNAS. 2007;104(49):19458-19463 6. Leitner J. Eur J Immunol. 2009;39:1754-1764. 7. Janeway CA, et al. Immunobiology: The
Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004
9
Immuno-Oncology:
Immune System Activating Pathways
Natural Killer Cell
T Cell
CD40L
CD137
CD137
SLAMF7
CD28
OX40
•
•
•
Activating pathways enable cytotoxic activity by binding to receptors or ligands on APCs; they can also be
expressed or preferentially upregulated by tumor cells1-4
Several activating receptors are thought to be involved in regulating NK Cell activity, including CD137 and
SLAMF71,2
T-cell activity may be regulated by pathways, including CD40, CD137, CD28, and OX403,4
APC, antigen-presenting cell; NK, natural killer.
1. Long EO et al. Annu Rev Immunol. 2013;13:227–258. 2. Benson DM Jr et al. J Clin Oncol. 2012;30:2013-2015.
3. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 4. Kirkwood JM, et al. CA Cancer J Clin. 2012;62(5):309-335.
10
Immuno-Oncology:
Immune System Inhibitory Pathways
Natural Killer Cell
T Cell
LAG-3
KIR
CTLA-4
B7-H3
receptor*
PD-1
•
•
•
Tumors may enhance inhibitory pathways to block NK cell and T-cell activation1-3
Several inhibitory receptors are thought to be involved in regulating NK cell activity, including inhibitory
KIRs2,3
T-cell activity may be negatively regulated by pathways including LAG-3, CTLA-4, B7-H3, and PD-12
*Defined receptors are not yet known and precise mechanism of T-cell inhibition by B7-H3 is currently unknown.
KIR, killer-cell immunoglobulin-like receptor; NK, natural killer.
1. Long EO et al. Annu Rev Immunol. 2013;31:227-258.
2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
3. Kirkwood JM et al. CA Cancer J Clin. 2012;62(5):309-335.
11
Immune Surveillance: Identification and Elimination of
Cancer Cells by the Immune System1-5
Priming/
T-cell activation
Antibody
production
Priming APC
activation
NK cell trafficking
& tumor killing
Antigen
release
Activated T-cell
migration to tumor
and tumor killing
Tumor cells
APC, antigen-presenting cell; NK, natural killer.
1. Abbas AK et al. Cellular and Molecular Immunology. 7th ed. Philadelphia, PA: Elsevier Saunders;2012.
2. Mellman I et al. Nature. 2011;480:480-489.
3. Boudreau JE et al. Mol Ther. 2011;19(5):841-853.
4. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY:
Garland Science; 2001.
5. Pardoll DM. Nat Rev Cancer. 2012;12:252-264.
12
B Cell–Mediated Cytotoxicity
B cells1
Activated
B cells
Immune cells that bind free-floating
antigens in the blood or lymph
through B-cell receptors
Once activated, B cells
differentiate to become plasma
cells, which can secrete large
quantities of antibodies against
a specific antigen1
Mature
B cell
Natural Killer cells1,2
Tumorassociated
antigens
Tumor cells
Cytotoxic lymphocytes that
attack infected or malignant
cells based on recognition of
antibodies on a cell surface
NK cells
Apoptotic
tumor cell
NK, natural killer.
1. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY:
Garland Science; 2001.
2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
13
T Cell–Mediated Cytotoxicity
T cells1,2
Antigen-presenting cells1,2
Inactive
T cell
Take up antigens from infected
or malignant cells and process
them into shorter peptide
segments
Activated
T cells
APC
APCs present antigens to naïve
T cells, which can recognize
tumor-associated antigens
Together with a second,
positive co-stimulation signal,
T cells become activated…
Tumorassociated
antigens
Tumor
cells
Apoptotic
tumor cell
…and play a major role in
killing infected or malignant
cells when activated
APC, antigen-presenting cell.
1. Mellman I et al. Nature. 2011;480(7378):480-489.
2. Boudreau JE et al. Mol Ther. 2011;19(5):841-853.
14
Immune Evasion in the Tumor Microenvironment
• The tumor microenvironment, a network of cells and structures that surround a tumor, creates
conditions that may foster tumor growth and immune evasion1,2
• Immune cell activity is regulated by multiple activation and inhibition pathways that modulate the
duration and level of the immune response2
• Tumors may target these pathways to alter the immune system’s response to cancer cells, resulting
in tumor evasion of the immune system3
APC
Active T cell
Tumorassociated
antigens
Tumor cells
APC, antigen-presenting cell.
1. Gajewski TF et al. Nat Immunol. 2013;14(10):1014-1022.
2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
3. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
Inactive T cell
15
Immunotherapies Encompass a Wide
Variety of Classes
Immunotherapy1,2
Passive
(Designed to act on the tumor)
Antitumor
mAbs
• Tumor-directed
mAbs
Adoptive
• Cell therapies
Active
(Designed to act on the immune system itself)
Cytokines
• Interleukins
• Interferons
Therapeutic
cancer vaccines
I-O
therapies
• Cell-based
• Single antigen/
peptide-based
Immune effector
cell modulators
• Checkpoint
inhibitors
• Co-stimulatory
agonists
I-O, immuno-oncology; mAb, monoclonal antibody.
1. Finn OJ. Ann Oncol. 2012;23(suppl 8 ):viii6-viii9.
2. Mellman I et al. Nature. 2011;480:480-489.
13
Immunotherapy Agents
cytokines
Interleukin 2
• Has pleiotophic effects on both cytotoxic T cell
function as well as Treg cell maintenance
• High dose – promotes CD8+ effector T cell and
natural killer (NK) cytolytic activity and promotes
differentiationof CD4+ cells into T helper
subclasses
• Lower Dose – preferentially expands Treg
populations and inhibits the formation of Th17
cells implicated in autoimmunity
Immunotherapy Agents
cytokines
Interleukin 2 (cont.):
• High dose achieved durable responses in
a small percentage of patients with
metastatic renal cell carcinoma and
melanoma
• First example of an immunotherapy that
could eliminate cancer cells
Immunotherapy Agents
cytokines
Interferon alpha 2B:
• Promotes TH-1-mediated effector
cell responses such as IL-12
secretion
• Used in the past as an adjuvant
treatment for high risk melanoma ? impact on long term survival
Immunotherapy Agents
cytokines
Lenalidomide and Pomalidomide:
• Mediate an antitumor effect largely
via the cereblon-mediated
destruction of Ikaros-family proteins
which in turn inhibit IL-2 secretion
• Prolong survival in multiple
myeloma
LAG-3 (aka CD223) is an immune “checkpoint” molecule.
1
• It can inhibit T-cell activity and serve as a modulator of T-cell activation.1,2
APC
Inactive T cell
MHC
LAG-3 - - -
CTLA-4 is an immune “checkpoint” receptor that plays a key role in modulating T-cell
function.1,3
• Interaction of CTLA-4 on T cells with its ligand CD80 (aka B7-1) and CD86 on APCs leads
to T-cell inhibition.1,3
APC
CD80 or CD86 ligand
IMMUNE SYSTEM PATHWAYS: INHIBITION
Known molecules involved in inhibition
Inactive T cell
CTLA-4 receptor ---
21
1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264 2. Workman CJ and Vignali DAA. Eur. J Immunol. 2003;33:970-979 3. Hastings, WD et al. Eur J Immunol. 2009 September: 39(9): 2492-2501
Immunotherapy Agents
checkpoint inhibitors
CTLA 4 inhibitors:
• Considered a physiologic brake on
CD4+ and CD8+ T cell activation
• Ipilimumab –first check point
inhibitor to be FDA approved, based
on its ability to prolong survival in
metastatic melanoma
• Also has a survival impact on high risk
Stage 3 melanoma
B7-H3 (a member of the B7 family) is thought to be an immune “checkpoint” pathway.
• It may inhibit the T-cell response beyond CD80/CD86 T-cell response.2
• Precise mechanism is under investigation.
APC
Inactive T cell
- - - B7-H3
???
PD-1 is an immune “checkpoint” receptor that inhibits the T-cell response and plays a
1
IMMUNE SYSTEM PATHWAYS: INHIBITION
Known molecules involved in inhibition
key role in modulating T-cell function.1
T cell
Tumor cell
- - - PD-1
PD-L1 or PD-L2
23
1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264 2. Leitner J, et al. Eur J Immunol. 2009;39(7):1754-1764
Immunotherapy Agents
checkpoint inhibitors
PD-1:
• Expressed on the surface of multiple tissue
types and many tumor cell types
• Its interaction with PD ligand (1 or 2):
• Directly inhibits apoptosis of the tumor cell
• Promotes T effector cell exhaustion
• Serves as a brake on unrestrained cytotoxic T effector cell
function
Immune Evasion in the Tumor Microenvironment
• The tumor microenvironment, a network of cells and structures that surround a tumor, creates
conditions that may foster tumor growth and immune evasion1,2
• Immune cell activity is regulated by multiple activation and inhibition pathways that modulate the
duration and level of the immune response2
• Tumors may target these pathways to alter the immune system’s response to cancer cells, resulting
in tumor evasion of the immune system3
APC
Active T cell
Tumorassociated
antigens
Tumor cells
APC, antigen-presenting cell.
1. Gajewski TF et al. Nat Immunol. 2013;14(10):1014-1022.
2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
3. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
Inactive T cell
25
Immunotherapy Agents
PD-1 inhibitors
Nivolumab (Opdivo):
1. Improved survival and less toxic as compared to
docetaxel in chemotherapy pretreated patients with
squamous nonsmall cell lung cancer (Checkmate-057 582 patients – ASCO 2015 LBA 109)
2. Improved survival (9.2 versus 6 months; p= 0.00025) and
less toxic as compared to docetaxel in chemotherapy
pretreated patients with nonsquamous nonsmall cell lung
cancer (Checkmate-017 264 patients)
Immunotherapy Agents
PD-1 inhibitors
Nivolumab (Opdivo):
3. Improved progression free survival (PFS) as first line
monotherapy or in conjunction with ipilimumab therapy
in metastatic melanoma, as compared to ipilimumab alone
(Checkmate-067 – 945 patients)
Immunotherapy Agents
PD-1 inhibitors
Pembrolizumab (Keytruda):
1. Approved by the FDA in 2014 for the treatment of
patients with metastatic melanoma following
treatment with BRAF inhibitors and/or ipilimumab
(Keynote 001 – Lancet 2014;384:1109-1117)
2. Ongoing trials in nonsmall cell lung cancer
Immunotherapy Agents
PD-1 inhibitors
MPDL3280A (Genentech/Roche):
1. A human mAB that targets PD-L1
2. It prevents binding of PD-L1 to its receptor (PD-1 and
B7-1), thereby restoring T cell activity and proliferation
3. Effective and relatively safe in several early phase lung
cancer trials
Immunotherapy Agents
PD-1 inhibitors
Tumor types in which these agents may be effective:
1. Metastatic melanoma
2. Nonsmall cell lung cancer
3. Renal cell carcinoma
4. Hodgkin’s Disease
5. Hepatocellular carcinoma
6. Triple negative breast cancer
7. Ovarian cancer
8. Certain colorectal cancers
Potential Patterns of Response to I-O Therapy
Therapies that affect the immune system may not induce a measurable impact on tumor growth
immediately after administration. Potential effects may be seen weeks to months after initial
administration. The potential patterns of response to I-O therapies that modulate T-cell activity are1,2:
Immediate response3
Lack of tumor shrinkage but a slowing
of tumor progression3
Early but clinically insignificant progression3
Tumor regression after early radiographical
progression that may be caused by T cells
infiltrating the tumor site or appearance of
new lesions upon imaging3,4
There is also the potential that patients may not respond to therapy.
I-O, immuno-oncology.
1. Hoos A et al. OncoImmunol. 2012;1:334-339. 2. Aarntzen EHJG et al. Cell Mol Life Sci. 2013;70:2237-2257.
3. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420. 4. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
31
Non-Conventional Response and I-O Therapy
Apparent progression upon radiographic imaging after initial I-O therapy can actually be a
sign of non-conventional response to I-O therapy. This response may occur when T cells
infiltrate the tumor
site and cause tumors to flare or appearance of new lesions
1,2
upon imaging.
I-O therapy
Tumor cells
T cells
infiltrating the
tumor site
Appearance of new
lesions upon imaging
I-O, immuno-oncology.
1. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420.
2. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
32
Differentiating Disease Progression From
Non-Conventional Response With I-O Therapy
• T-cell infiltration can cause tumors to flare or new lesions may appear upon imaging1
• Considerations that may indicate disease progression vs. non-conventional response
include1,2:
Disease Progression
Non-Conventional Response
Performance status
Deterioration of performance
Remains stable or improves
Systemic symptoms
Worsen
May or may not improve
Symptoms of tumor
enlargement
Present
May or may not be present
Tumor burden
Baseline
New lesions
Increase
Appear and increase in size
Increase followed by response
Appear then remain stable and/or
subsequently respond
Biopsy may reveal
Evidence of tumor growth
Evidence of T-cell infiltration
I-O, immuno-oncology.
1. Wolchok JD et al. Clin Cancer Res. 2009;15(23):7412-7420.
2. Eisenhauer EA et al. Eur J Cancer. 2009;45(2):228-247.
23
Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions related to T-cell modulation may affect
certain organ systems1
1.
2.
3.
4.
5.
Nervous system2
Eyes1,3
Skin1,2,4
Respiratory system1,2
Liver2,4
Endocrine system2,4
Gastrointestinal tract1-4
Hematopoietic cells5
Amos SM et al. Blood. 2011;118(3):499-509.
Chow LQ. Am Soc Clin Oncol Educ Book. 2013:280-285.
Robinson MR et al. J Immunother. 2004;27(6):478-479.
Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377.
Lin TS et al. J Clin Oncol. 2010;28(29):4500-4506.
34
Clinical Implications of Immune-Mediated ARs
Since I-O can increase immune system activity, the potential exists for toxicity against
healthy tissues in addition to cancer cells1
• ARs can be serious and potentially fatal2,3
– An AR is any unfavorable medical occurrence temporally associated with the use of a
medical treatment2
– Serious ARs are defined as any AR that requires hospitalization, is life-threatening,
results in death, or otherwise causes persistent or significant incapacity3
• Remain vigilant throughout and after treatment4
– Educate and encourage patients to monitor for and report symptoms of
immune-mediated ARs
Not all immune-mediated ARs will require permanent cessation of
therapy. Providing optimal care for your patients includes following
management algorithms for certain immune-mediated ARs.4
AR, adverse reaction; I-O, immuno-oncology.
1. Amos SM et al. Blood. 2011;118(3):499-509.
2. NCI. Radiation therapy for cancer. V4.0. US Department of Health and Human Services. 2010.
3. FDA. What is a serious adverse event? http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm.
Accessed January 28, 2015.
4. Gelao L et al. Toxins. 2014;6:914-933.
35
Cancer Therapy 2015
Prognostic Marker:
1) Used to classify an individual patient’s risk of, or time to,
cancer death and/or other disease events independent of the
effects of treatment.
2) Can also be used to determine the need for further treatment
• Patients at very low risk of disease events can safely
avoid treatment if risks of adverse events outweigh the
estimated benefits.
•
Alternatively, high-risk patients may benefit from a more
aggressive treatment regimen
3) In some cases, a prognostic marker also predicts treatment
response because it is also a therapeutic target (i.e, it is also a
predictive marker).
• For example, estrogen receptor expression provides
prognostic information in women with early breast
cancer and RCTs have provided evidence that it predicts
response to hormonal therapy
Cancer Therapy 2015
Prognostic Marker:
• Usually an indicator of growth, invasion and metastatic
potential
• Examples:
•
•
•
•
•
•
Weight loss
Poor performance status
Sites of metastases (bone, CNS, etc.)
Hormone receptor positivity in breast cancer
Weight loss
HER 2 over expression in breast cancer
Cancer therapy 2015
Predictive Marker:
1) Used to classify response to specific treatment options; predictive markers
are used to guide the selection of treatment and identify targets for the
development of new molecular-targeted therapies.
2) Used to select the most appropriate treatment by identifying patients most
likely to respond and avoiding treatment for patients unlikely to respond or
those at unacceptably high risk of adverse events.
3)
Classify patients according to their predicted response or resistance to a
treatment
4)
The use of predictive markers clearly has enormous clinical implications to
optimize the selection of treatments to those patients most likely to respond
and avoid the use of treatment in patients unlikely to respond, or those at high
risk of treatment-related adverse events.
5)
Non-responders may benefit from the earlier use of alternative therapies or can
be identified as a population in need for the development of new treatments
Cancer therapy 2015
Predictive Marker:
1. Such markers are usually within the target of the treatment or
the surrounding stroma
Or
2. Serve as modulators or epiphenomena related to expression
and/or function of the target
Examples:
• Hormone receptor positivity in breast cancer
• HER 2 overexpression in breast cancer
• EGFR mutations and ALK gene rearrangements in lung cancer
• ?PD-1 ligand expression in lung cancer
Cancer therapy 2015
• Assay Development
• Analytical validation
• Assess assay performance, reproducibility,
sensitivity and specificity
• Clinical validation
• Prospective-retrospective validations
(investigators blinded to outcome data)
• Clinical utility
• Use of convenience samples and data –
subject to bias
• Second prospective-retrospective study
Investigators again blinded to outcome)
• Randomized prospective trial
.
Predictors of response to
immune-based therapy
PD-1 inhibitors:
1.
PD-L1 expression – efficacy of nivolumab was more significant in
pretreated patients with nonsquamous nonsmall cell lung cancer
(Checkmate 057).
2.
PD-L1 expression was not linked with efficacy outcome in
squamous nonsmall cell lung cancer (Checkmate 017)
3.
PD-L1 expression in tumors correlates with response to
MPDL3280A (a PD-L1 inhibitor) in the POPLAR Study (ASCO
2015, abstract 8010)
4.
MMRD (mismatch repair deficiency) – correlation with benefit in a
phase 2 study of patients with metastatic colorectal cancer and
other tumor types with MMRD (ASCO 2015, abstract LBA 100)
Cancer therapy 2015
summary
PD-1 inhibitors and PD- L1 inhibitors are
emerging as novel immune modulating agents
for the treatment of various refractory cancers
The side effects associated with these agents are
autoimmune in nature (pneumonitis, hepatitis,
colitis, dermatitis, thyroiditis, etc)
No definitive predictive marker for PD-I
inhibitors has emerged as of yet; the role of PDL1 remains controversial
Immuno oncology Is an Evolving
Cancer Treatment Modality
Chemotherapy/
Targeted therapy
Surgery
Radiation
Immuno-Oncology
The Conquest of
Cancer
1. Knowledge of the molecular phenotype of the
cancer
2. Knowledge of the pharmacogenomics of the
patient
3. Knowledge of the angiogenic profile/status of
the cancer
4. Knowledge of the immunocompetence of the
patient
5. Understanding of the comorbities of the patient
The Conquest of
Cancer
1. Knowledge of the molecular footprint of the tumor
1.
2.
Susceptibility to one or a combination of targeted
therapies
Needs to be in real time and with the understanding of
possible metastatic site heterogeneity
The Conquest of
Cancer
2. Knowledge of the pharmacogenomics of the patient
1.
2.
Verification that the therapeutic molecule will achieve
therapeutic concentrations and will be appropriately
metabolized
Knowledge of drug/drug interactions during
administration of the therapeutic agent
The Conquest of
Cancer
3. Knowledge of the angiogenic profile/status of the
tumors
1.
Determine that in fact the appropriate targeted agent,
metabolized appropriately, can effectively arrive at its
target at every site
The Conquest of Cancer
4. Knowledge of the immunocompetence of the patient
Some tumors co-opt the patient’s immune system so
as to be able to evade it
A perfect vaccine may not work in every patient in light of a
different level of immune competency, which in turn can be
impact by:
1.
2.
Age
Exposure to prior immunosuppressive/immune destroying
agents
The Conquest of Cancer
5. Understanding of the co-morbities of the patient
The perfect treatment, in the perfect context
(pharmacogenomics, etc, that arrives to target (appropriate
angiogenic profile), but exacerbates two of the four comorbities that the patient has, thus not conferring a survival
benefit
The Conquest of
Cancer
1. Knowledge of the molecular phenotype of the
cancer
2. Knowledge of the pharmacogenomics of the
patient
3. Knowledge of the angiogenic profile/status of
the cancer
4. Knowledge of the immunocompetence of the
patient
5. Understanding of the comorbities of the patient