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Cancer Immunotherapy: Fundamental Concepts and Emerging Role Urology Perspective. Learning Objectives. Review the evidence supporting the immune system’s role in cancer Review the characteristics of an immune response Describe mechanisms of immunotherapy

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learning objectives
Learning Objectives
  • Review the evidence supporting the immune system’s role in cancer
  • Review the characteristics of an immune response
  • Describe mechanisms of immunotherapy
  • Discuss treatment considerations of cancer immunotherapy
everyday functions of the immune system
Everyday Functions of the Immune System
  • Principal function—prevent/eradicate infections
  • Continuouslysurveilsfor foreign antigens
  • Initial defenses are nonspecific, while specialized defenses mount a targeted response

Courtesy of Science Source

Courtesy of Science Source

Courtesy of Science Source

Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

immune response key components
Immune Response: Key Components
  • Antigen
    • Substance that generates an immune response (eg, proteins of pathogens or tumors)
  • Antigen presenting cells (APCs)
    • Identify and uptake foreign antigens
    • Present them to T cells
  • T cells
    • Recognize and destroy cells containing foreign antigen
  • B cells
    • Produce antibodies specific to foreign antigens
  • Antibody
    • Protein that can identify and neutralize foreign antigens
  • Cytokines
    • Proteins that are naturally secreted by immune system cells

Abbas AK,Lichtman AH. Basic Immunology. 3rd ed. 2011.

initiation of immune response key components
Initiation of Immune Response: Key Components

Effector cells:

  • Activate other immune cells
  • Kill “target cells”

Antigenfragments

Antigen

NaiveT-cell

Antigen receptors

ActivatedT-cell

Memory cells:

  • Circulate for months  years
  • Ready to rapidly respond to same antigen again

Antigen presenting cell (APC)

Antigenrecognition

Activated APC

T-cellinteraction

T-cell activation

T-cells become specialized

Replication of antigen-specific T-cells

Activation

  • Lymphoid Organs

Adapted from Abbas AK, Lichtman AH.

  • Peripheral Tissues

Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

hallmarks of cancer pathogenesis
Hallmarks of Cancer Pathogenesis
  • Evading growth suppressors
  • Activating invasion and metastasis
  • Avoidingimmune
  • destruction

Hallmarks of Cancer Pathogenesis (2011)1,2

  • Enabling replicative immortality
  • Deregulatingcellularenergetics
  • Sustaining proliferative signaling
  • Inducingangiogenesis
  • Resisting cell death

1. Hanahan D, Weinberg RA. Cell. 2011;144:646-674.

2. Hanahan D, Weinberg RA. Cell. 2000;100:57-70.

increased incidence of cancer in immunocompromised individuals
Increased Incidence of Cancer in Immunocompromised Individuals
  • Malignant tumors develop in individuals with compromised immune systems1-3

Tumor/cancer risk in transplant patients compared to general population1-3

Non-melanoma skin cancer

20-fold and beyond

Non-Hodgkin’s lymphoma

Kidney cancer

15-fold

Melanoma

8-fold

Hepatobiliary cancer

5-fold

Bladder cancer

3-fold

Testicular cancer

Breast cancer

2-fold

Prostate cancer

Colon cancer

0

5

10

15

20

Fold-increase in tumor/cancer risk

Kasiske BL, Wang C, et al. Am J Transplant. 2004;4(6):905-913.

Le Mire L, Wojnarowska F, et al. Br J Dermatol. 2006;154(3):472-477.

Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

immune cells within tumors predict overall survival
Immune Cells Within Tumors Predict Overall Survival
  • T-cell infiltration within tumors predicts overall survival (OS) in multiple cancer types including bladder cancer1-3

Infiltration of T cells Predicts Survival of Patients With Muscle-Invasive Bladder Cancer1

T cells (CD8) <8 (median=13 months)

1.0

T cells (CD8) ≥8 (median >80 months)

0.8

0.6

Prop. Surviving Without Disease

0.4

0.2

P<0.001

0.0

0

20

40

60

80

Time in Months

Reprinted from Sharma P, Sato E, et al.1

Sharma P, Sato E, et al. Proc NatlAcadSci U S A. 2007;104(10): 3967-3972.

Zhang L, Coukos G, et al. N Engl J Med. 2003;348(3):203-213.

Galon J, Pagès F, et al. Science. 2006;313(5795):1960-1964.

immunotherapy proven effective in cancer
Immunotherapy Proven Effective in Cancer
  • Therapies that engage the immune system have been shown to improve patient survival in randomized, phase 3 cancer trials1-3
  • Immunotherapies approved by the FDA to treat certain cancers4
    • Cytokines
    • Monoclonal antibodies
    • Checkpoint inhibitors
    • Therapeutic vaccines

Robert C, Wolchok JD, et al. N Engl J Med. 2011;364(26):2517-2526.

Hodi FS, Urba WJ, et al. N Engl J Med. 2010;363(8):711-723.

Kantoff PW, Schellhammer PF, et al. N Engl J Med. 2010;363(5):411-422.

Mellman I, Dranoff G, et al. Nature. 2011;480 (7378):480-489.

dynamics between cancer and the immune system
Dynamics Between Cancer and the Immune System
  • Immune system and cancer interact in a dynamic process, known as the 3 E’s
    • Elimination (immune system eradicates cancer cells)
    • Equilibrium (immune system controls cancer outgrowth)
    • Escape (cancer overwhelms the immune system)

Immune Protection

Immune Evasion

Dunn GP, Schreiber RD, et al. Nat Rev Immunol. 2006;6(11):836-848.

elimination immune system eradicates cancer cells 1
Elimination: Immune System Eradicates Cancer Cells1

Immune Evasion

Immune Protection

  • A natural process involved with early disease2

Immune cells

Abnormal cells/tissue

Normal cells/tissue

Adapted from Dunn GP, Schreiber RD, et al.

Dunn GP, Schreiber RD, et al. Nat Rev Immunol. 2006;6(11):836-848.

Trinchieri G. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011.

13

equilibrium immune system controls cancer cells 1
Equilibrium: Immune System Controls Cancer Cells1

Immune Protection

Immune Evasion

  • Occurs with later stage tumors2
  • Represents a balanced “dynamic” between the immune system and cancer1,2

Immune cells

Abnormal cells / tissueoutgrowth controlled

Adapted from Dunn GP, Schreiber RD, et al.1

Dunn GP, Schreiber RD, et al. Nat Rev Immunol. 2006;6(11):836-848.

Trinchieri G. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011.

14

escape cancer cells evade immune system
Escape: Cancer Cells Evade Immune System

Immune Protection

Immune Evasion

  • Tumor cell variants grow, resulting in progressive disease

Immune cells

Abnormal cells / tissue

Abnormal cells / tissuecontinue to replicate

Adapted from Dunn GP, Schreiber RD, et al.

15

Dunn GP, Schreiber RD, et al. Nat Rev Immunol. 2006;6(11):836-848.

features of an effective immune response 1 2
Features of an Effective Immune Response1,2
  • Specificity
  • Trafficking
  • Adaptability
  • Target elimination
  • Durability (immune memory)

Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

Drake CG. Nat Rev Immunol. 2010;10(8);580-593.

specificity
Specificity

Flu Virus Year 1

  • Ability to recognize and mount a specific response to distinct antigens1
  • Example2
    • Seasonal flu mutates surface antigens
    • Annual vaccination allows the immune system to effectively recognize and target the specific flu strain

Flu virus surface antigens

Antibodies targeted to Year 1 antigens

Flu Virus Year 2

Flu virus surface antigens

Antibodies targeted to Year 2 antigens

AbbasAK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

Grebe KM, Bennink JR, et al. Microbes Infect. 2008;10(9):1024-1029.

trafficking
Trafficking
  • Ability of activated immune system cells to migrate to particular antigens throughout the body1,2
  • Example
    • Following exposure to activated APCs, naive T cells become activated1
    • Activated T cells are mobilized to areas containing antigen1,2

Reinhardt RL, Jenkins MK, et al. Nature. 2001;410(6824):101-105.

Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

Courtesy of Science Source

adaptability
Adaptability
  • Allows for a broader immune response1 (eg, immune response to additional antigens) 2

PSMA

PSCA

Tumor

PAP

ActivatedAPC

Antigen 2

Tumor

Antigen 1

APC

MUC-1

Naive T cell

T cell

Activated T-cell target and kill tumor cell

APC takes up additional released antigens

Activated APC presents antigen to naive T cell

Adapted from Gulley JL. Hum Vaccin Immunother. 2013;9(1):1-3.

PSMA, prostate-specific membrane antigen; PSCA, prostate stem cell antigen; PAP, prostatic acid phosphatase; MUC-1, mucin-1.

Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

Nesslinger NJ, Gulley JL, et al. Clin Cancer Res. 2010;16(15):4046-4056.

immune response target elimination
Immune Response: Target Elimination
  • Ability of immune cells to destroy their target (eg, cancer cells)1,2
    • Usually via induction of apoptosis3

Target cell death3:

Scanning Electron Micrograph showing T cells inducing a target cell to undergo apoptosis

T cell

T Cell

Apoptotic Bodies

Target Cell (eg, cancer cell)

Courtesy of sciencesource.com

Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

Boissonnas A, Amigorena S, et al. J Exp Med. 2007;204(2):345-356.

Trapani JA, Smyth MJ. Nat Rev Immunol. 2002;2(10):735-747.

durability immune memory
Durability (Immune Memory)
  • Ability of immune system to recognize an antigen to which it has previously been exposed and provide long-lasting protection against it1

Shown is the durable virus-specific T-cell response after smallpox vaccination2

Percentage

1. Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.

2. Hammarlund E, Slifka MK, et al. Nat Med. 2003;9(9):1131-1137.

immunotherapy
Immunotherapy
  • Treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases
  • Cytokines
  • Monoclonal antibodies
  • Checkpoint inhibitors
  • Therapeutic vaccines

National Cancer Institute. Cancer terms. http://www.cancer.gov/dictionary/?print=1&cdrid=45729. Accessed October 5, 2012.

Mellman I, Dranoff G, et al. Nature. 2011;480(7378):480-489.

the renaissance of immunotherapy 1 5
The Renaissance of Immunotherapy1-5

Enthusiasm Phase

Skepticism Phase

Renaissance Phase

1978-1985

1985-1997

1997-

20101st cellular immunotherapy approved for CA

1992IL-2 (cytokine) approved for CA

1986IFN-α (cytokine) approved for CA

19851st study with adoptive T-cell transfer in CA

19761st study with BCG in bladder CA

1890s 1st CA vaccine developed (Coley)

1990s Discovery of role of checkpoint inhibitors in CA

1978 Discovery of tumor specific mABs

20111st checkpoint inhibitor approved for CA

1997 1st mAB approved for CA

1973 Discovery of the dendritic cell (Steinman)

Adapted with permission from Lesterhuis WJ, Punt CJ, et al2 and Kirkwood JM, Gogas HJ, et al. J ClinOncol. 2008;26(20):3445-3455.

BCG, Bacille Calmette-Guerin; mABs, monoclonal antibodies; CA, cancer; IFN-α, interferon alpha; IL-2, interleukin-2

Kirkwood JM, Ferrone S, et al. CA Cancer J Clin. 2012;62(5):309-335.

Lesterhuis WJ, Punt CJ, et al. Nat Rev Drug Discov. 2011;10(8):591-600.

Krummel MF, Allison JP. J Exp Med. 1995;182(2):459-465.

Lotze M. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011

Leget GA, Czuczman MS. CurrOpinOncol. 1998;10(6):548-551.

cytokines
Cytokines
  • Proteins that are naturally secreted by immune system cells1
  • Mechanism of action2
    • Interleukin-2 (IL-2) stimulates T-cell proliferation
  • Examples2
    • Interleukins, interferons
  • Efficacy3
    • IL-2 demonstrated activity in a number of cancer types (eg, colon, breast, renal cell carcinoma [RCC])
    • ~7% of RCC patients show a complete response; this response may also be durable

IL-2 Stimulation of T-cell Proliferation2

IL2 Receptor

Cell Proliferation

  • Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.
  • Bachmann MF, Oxenius A. EMBO Rep. 2007;8(12):1142-1148.
  • Lotze M. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011.
monoclonal antibodies mabs
Monoclonal Antibodies (mABs)
  • Proteins designed to bind to specific substances in the body1
  • Mechanism of action2,3
    • Differs between agents
    • Bind to their specific target antigen ultimately causing cell death
  • Efficacy
    • Demonstrated improvement in survival in different cancers4,5
    • Demonstrated prevention of skeletal-related events5

Potential mechanisms of mABs in cancer

T cell

Cytokine-mAb

Tumor cell

Toxin-mAb

Drug-mAb

Receptor

Tumor cell death

Adapted from Kirkwood JM, Ferrone S, et al. CA Cancer J Clin. 2012;62(5):309-335.

  • NCI. www.cancer.gov/dictionary. Accessed January 11, 2013.
  • Cheson BD, Leonard JP. N Engl J Med. 2008;359(6):613-626.
  • Weiner LM, Wang S. Nat Rev Immunol. 2010;10(5):317-327.
  • Slamon DJ, Norton L, et al. N Engl J Med. 2001;344(11):783-792.
  • Smith MR, Goessl C, et al. Lancet. 2012;379(9810):39-46.
checkpoint inhibitors
Checkpoint Inhibitors
  • Inhibit tumor-induced suppression of T-cell activation or function1,2
  • Mechanism of action1,2
    • Antibodies target immune checkpoints to enhance antitumor response
  • Examples1,2
    • CTLA-4 and PD1
  • Efficacy3-6
    • Extends OS in certain metastatic diseases
    • A significant effect on PFS not consistently observed

Activated APC

CTLA4 receptor

Naive T cell

CTLA4 antibodies

Adapted with permission from Sharma P, Allison JP, et al.2

  • CTLA4 and PD1 blunt immune response to tumor
  • Checkpoint inhibitors direct antibodies against them to enhance antitumor response

PD1

receptor

PD1 antibodies

  • CTLA-4, cytotoxic T lymphocyte-associated antigen 4; PD1, programmed death 1
  • Pardoll D. Nat Rev Cancer. 2012;12(4):252-264.
  • Sharma P, Allison JP, et al. Nat Rev Cancer. 2011;11(11):805-812.
  • Hodi FS, Urba WJ, et al. N Engl J Med. 2010;363(8):711-723.
  • Robert C, Wolchok JD, et al. N Engl J Med. 2011;364(26):2517-2526.
  • Brahmer JR, Wigginton JM, et al. N Engl J Med. 2012;366(26):2455-2465.
  • Topalian SL, Sznol M, et al. N Engl J Med. 2012;366(26):2443-2454.
therapeutic cancer vaccines
Therapeutic Cancer Vaccines
  • Mechanism of action1
    • Activation of T cells to seek out and destroy target cancer cells
  • Efficacy2,3
    • Significantly extended OS in certain metastatic diseases without an effect on PFS

Naive T cell

Activated APC

Activated T cell

Normal cells/tissue

Abnormal cells/tissue

  • Drake CG. Nat Rev Immunol. 2010;10(8):580-593.
  • Kantoff PW, Schellhammer PF, et al. N Engl J Med. 2010;363(5):411-422.
  • Kantoff PW, Godfrey WR, et al. J Clin Oncol. 2010;28(7):1099-1105.
goal of therapeutic cancer vaccines
Goal of Therapeutic Cancer Vaccines

“Cancer treatment vaccines are designed to treat cancers that have already developed. They are intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment."

- NCI (2011)

National Cancer Institute. Cancer vaccines. http://www.cancer.gov/cancertopics/factsheet/Therapy/. Accessed December 15, 2012.

characteristics of immunotherapy
Characteristics of Immunotherapy

Rescigno M, Curigliano G, et al. BiochimBiophysActa. 2007;1776(1):108-123.

characteristics of therapeutic vaccines 1 2
Characteristics of Therapeutic Vaccines1,2
  • Gulley JL. Hum Vaccin Immunother. 2013;9(1):1-3.
  • Slovin S. Clin Adv HematolOncol. 2012;10(2):90-100.
immunotherapy treatment considerations
Immunotherapy: Treatment Considerations
  • Relative efficacy of immunotherapy may be greater with lower tumor burden1,2
  • Patient given immunotherapy earlier in disease course might have a better outcome3

Tumor Growth Rate

Expected clinical outcome if no treatment is provided

B

Death

A

A

Patient given a vaccine earlier

Tumor Burden

B

Patient given a vaccine later

Time

Adapted with permission from Gulley JL, Drake CG.3

  • Kirkwood JM, Ferrone S, et al. CA Cancer J Clin. 2012;62(5):309-335.
  • Drake CG. Nat Rev Immunol. 2010;10(8):580-593.
  • Gulley JL, Drake CG. Clin Cancer Res. 2011;17(12):3884-3891.
potential role in combination therapy
Potential Role In Combination Therapy
  • Standard practice in oncology is the use of combination agents with different mechanisms of action1-3
    • Chemotherapy and mABs
    • Radiation and chemotherapy
    • Multiple chemotherapy regimens
  • Immunotherapy offers potential for synergy with other therapies1-6

Drake CG, Adler AJ, et al. Cancer Cell. 2005;7(3):239-249.

Mercader M, Kwon ED, et al. Proc NatlAcadSci USA. 2001;98(25):14565-14570.

Aragon-Ching JB, Gulley JL, et al. Front Biosci. 2007;12:4957-4971.

Vermorken JB, Hitt R, et al. N Engl J Med. 2008;359(11):1116-1127.

Slamon DJ, Norton L, et al. N Engl J Med. 2001;344(11):783-792.

Gulley JL, Drake CG. Clin Cancer Res. 2011;17(12):3884-3891.

immunotherapy an established treatment strategy
Immunotherapy: An Established Treatment Strategy
  • More than a dozen different immunotherapy agents have been approveda, with the majority over the last decade1-5
  • Immunotherapy agents currently approved target >10 different cancer types1-5

aNot inclusive of all immunotherapy classes.

Mellman I, Dranoff G, et al. Nature. 2011;480(7378):480-489.

Kirkwood JM, Ferrone S, et al. CA Cancer J Clin. 2012;62(5):309-335.

Lotze M. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011.

Sondak VK, Hauschild A, et al. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011.

Robinson MK, Weiner LM, et al. In: Cancer: Principles & Practice of Oncology. 9th ed. 2011.

35

immunotherapy future promise
Immunotherapy: Future Promise
  • Rapid increase in immunotherapy clinical research
    • Doubling of abstracts at major conferences from 2009 to 20121
    • Approximately 800 clinical trials in various phases ongoing2
      • eg, breast, colon, head and neck, kidney
  • Trials utilize agents alone and in combination with conventional therapies2

Courtesy of sciencephoto.com

  • SeekingAlpha.com. http://seekingalpha.com/article/667581-immunotherapy-comes-of-age-at-asco-2012. Accessed January 4, 2013.
  • ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed January 4, 2013.
summary
Summary
  • The immune system plays a critical role in controlling cancer1
  • Key features of an effective immune response include2
    • Specificity
    • Adaptability
    • Durability (immune memory)
  • Future clinical considerations
    • May elicit better immune system response if used earlier in disease3,4
    • Potential for durable clinical effects and synergy with subsequent therapies5-8
  • Vermorken JB, Hitt R, et al. N Engl J Med. 2008;359(11):1116-1127.
  • Slamon DJ, Norton L, et al. N Engl J Med. 2001;344(11):783-792.
  • Robert C, Wolchok JD, et al. N Engl J Med. 2011;364(26):2517-2526.
  • Mercader M, Kwon ED, et al. Proc NatlAcadSci USA. 2001;96(25):14565-14570.
  • Dunn GP, Schreiber RD, et al. Nat Rev Immunol. 2006;6(11):836-848.
  • Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011.
    • Kirkwood JM, Ferrone S, et al. CA Cancer J Clin. 2012;62(5):309-335.
    • Drake CG. Nat Rev Immunol. 2010;10(8):580-593.
questions
Questions?

MA-01.13.06.02