The Emerging Role of Immunotherapy in Cancer Care 2015 Renato V. La Rocca, MD, FACP Norton Cancer Institute Louisville, Kentucky

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 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

Lung

4.0

Colorectal

12.9Kidney andRenal Pelvis

12.1

Melanoma

16.1

5-year Survival in Advanced Cancers (%)1

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.

There is an ongoing need for new treatments and therapeutic modalities for patients with advanced cancers3

Bladder

5.5

5

Hallmarks of cancer

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

As normal cells progressively evolve to a neoplastic state, they can acquire a succession of hallmark capabilities1:

Sustaining proliferative signaling

Evading growth

suppressors

Activating invasion

and metastasis

Enabling replicative immortality

Inducing angiogenesi

s

Resisting cell death

Deregulating cellular

energetics*

Avoiding immune

destruction*

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

8 hallmarks of cancer1

*Emerging hallmarks

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

Through I-O research, therapies are being investigated in an attempt to utilize the body's own immune system to fight cancer1-3

Chemotherapy/Targeted therapy

Radiation

Immuno-OncologySurgery

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

Antigen-presenting

cells• take up antigens from

infected or malignant cells and processes them into shorter peptide segments2

• present antigen to T cells to mobilize an immune response2

Tumor-associated antigens

• are abnormal cell substances/proteins (tumor antigens) which can be recognized and responded to by the immune system1

T cells1

• have T-cell receptors, which can recognize tumor-associated antigens

• play a major role in killing infected or malignant cells when activated

• help perpetuate ongoing immune responses1. 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

Antibodies• are secreted by

activated B cells, called plasma cells1

• tag antigen-containing cells for attack by other parts of the immune system, or neutralize their targets directly by blocking important mechanisms1

B cells1

• display B-cell receptors, which can bind free floating antigens in the blood or lymph

• once activated, B cells differentiate to become plasma cells which can secrete large quantities of antibodies against a specific antigen1

1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004

NK cells1

• can recognize infected or malignant cells innately without contact with an antigen-presenting cell or antibody (this allows NK cells to launch rapid responses against stressed cells)

• can also attack based on recognition of antibodies on a cell surface

IMM

UN

E SYSTEM PATH

WAYS

Immune system pathways• 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

91. 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: TheImmune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004

Tumors may down-regulate co-stimulatory pathways.2-3

Co-stimulatory receptors include:

• CD28• CD40• OX40• CD137

Tumors may up-regulate immune checkpoints (inhibitory signaling pathways).2,3,5,6 Checkpoint pathway molecules include:• LAG-3• CTLA-4• B7-H3• PD-1

10

Immuno-Oncology:Immune System Activating Pathways

• 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

Natural Killer Cell T Cell

CD137

SLAMF7

CD40L

CD28

OX40

CD137

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.

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Immuno-Oncology:Immune System Inhibitory Pathways

Natural Killer Cell T Cell

LAG-3

PD-1

CTLA-4

• 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

KIR

B7-H3receptor*

*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.

Immune Surveillance: Identification and Elimination of Cancer Cells by the Immune System1-5

12

Priming APC activation

Antigenrelease

NK cell trafficking& tumor killing

Priming/T-cell activation

Antibodyproduction

Activated T-cellmigration to tumorand 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.

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B Cell–Mediated Cytotoxicity

B cells1

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

Natural Killer cells1,2

Cytotoxic lymphocytes that attack infected or malignant cells based on recognition of antibodies on a cell surface

Mature B cell

NK cells

Activated B cells

Apoptotic tumor cell

Tumor cells


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.

14

T Cell–Mediated Cytotoxicity

Antigen-presenting cells1,2

Take up antigens from infected or malignant cells and process them into shorter peptide segments

T cells1,2

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…

…and play a major role in killing infected or malignant cells when activated

Activated T cells

Apoptotictumor cell

Inactive T cell

APC

Tumor cells


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.

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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

Tumor cells

Active T cell

Inactive T cell


APC

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.

Immunotherapies Encompass a WideVariety of Classes

13

• Interleukins• Interferons

• Cell-based• Single antigen/

peptide-based

Immune effector cell modulators

• Checkpoint inhibitors

• Co-stimulatory agonists

Active(Designed to act on the immune system itself)

Immunotherapy1,2

• Tumor-directed mAbs

• Cell therapies

Passive(Designed to act on the tumor)

Therapeutic cancer vaccinesCytokines I-O

therapiesAntitumor

mAbs Adoptive

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.

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


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


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


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

IMM

UN

E SYSTEM PATH

WAYS: IN

HIBITIO

N

Known molecules involved in inhibitionLAG-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

211. 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

APC Inactive T cell

LAG-3 - - -

MHC

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 Inactive T cell

CTLA-4 receptor ---CD80 or CD86 ligand

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

IMM

UN

E SYSTEM PATH

WAYS: IN

HIBITIO

N

Known molecules involved in inhibitionB7-H3 (a member of the B7 family) is thought to be an immune “checkpoint” pathway.1

• It may inhibit the T-cell response beyond CD80/CD86 T-cell response.2

• Precise mechanism is under investigation.

231. Pardoll DM. Nat Rev Cancer. 2012;11:252-264 2. Leitner J, et al. Eur J Immunol. 2009;39(7):1754-1764

APC Inactive T cell

???- - - B7-H3

PD-1 is an immune “checkpoint” receptor that inhibits the T-cell response and plays a key role in modulating T-cell function.1

T cell Tumor cell

PD-L1 or PD-L2 - - - PD-1

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

25

Tumor cells

Active T cell

Inactive T cell


APC

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.

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)


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)


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


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


Tumor types in which these agents may be effective:1. Metastatic melanoma2. Nonsmall cell lung cancer3. Renal cell carcinoma4. Hodgkin’s Disease5. Hepatocellular carcinoma6. Triple negative breast cancer7. Ovarian cancer8. 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.

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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 upon imaging.

1,2

T cells infiltrating the

tumor site

Appearance of new lesions upon imaging

I-O therapy

Tumor cells

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.

Differentiating Disease Progression FromNon-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:

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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 responseAppear 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.

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Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions related to T-cell modulation may affect certain organ systems1

Nervous system2 Respiratory system1,2Eyes1,3 Skin1,2,4

Liver2,4 Hematopoietic cells5Endocrine system2,4 Gastrointestinal tract1-4

1. Amos SM et al. Blood. 2011;118(3):499-509. 2. Chow LQ. Am Soc Clin Oncol Educ Book. 2013:280-285. 3. Robinson MR et al. J Immunother. 2004;27(6):478-479. 4. Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377. 5. Lin TS et al. J Clin Oncol. 2010;28(29):4500-4506.

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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

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.

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

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 2015summary

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 PD-L1 remains controversial

Immuno oncology Is an Evolving Cancer Treatment Modality

Chemotherapy/Targeted therapy

Radiation

Immuno-OncologySurgery

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


1. Knowledge of the molecular footprint of the tumor

1. Susceptibility to one or a combination of targeted therapies

2. Needs to be in real time and with the understanding of possible metastatic site heterogeneity



1. Verification that the therapeutic molecule will achieve therapeutic concentrations and will be appropriately metabolized

2. Knowledge of drug/drug interactions during administration of the therapeutic agent


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



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. Age

2. Exposure to prior immunosuppressive/immune destroying agents


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 co-morbities that the patient has, thus not conferring a survival benefit


1. Knowledge of the molecular phenotype of the cancer


3. Knowledge of the angiogenic profile/status of the cancer


5. Understanding of the comorbities of the patient

Documents

The Emerging Role of Immunotherapy in Cancer Care 2015 Renato V. La Rocca, MD, FACP Norton Cancer Institute Louisville, Kentucky