Colorado Quarterly Coalition Meeting

Cancer Date: October 27, 2016 Time: 2:00pm - 4:00pm Coalition Facilitator: Dr. Madeleine Kane

Location American Society Office - Brooks Conference Center, 2255 S. Oneida St., Denver, CO

Remote information: Livestream Link: https://echo.zoom.us/j/7648943828 ​ ​ A phone number will be provided after logging in to the meeting

RSVP Here: https://www.eventbrite.com/e/colorado-cancer-coalition- quarterly-meeting-tickets-28188854623

Meeting Purpose Colorado Cancer Coalition and Task Force Updates

Time Topic Lead Notes

2:00 pm - Introductions 2:10 pm

2:10- 2:40 Coalition Updates Dr. Madeleine Kane ● Journey Connections Update ● New Committees to Join ○ Checkoff Communications ○ Resource/Fundraising ○ Resource Directory ○ Patient Advisory Committee ○ Symposium ○ Clinical Trials/Treatment Task Force ○ Interested in joining a committee? ● CCC Financials

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2:40- 3:00 Task Force Updates Task Force Chairs 3 Task Forces will provide updates. Other Task Force written updates are included in the agenda ● - PPT Slides ​ ● Survivorship - PPT Slides ​ ● Family History

3:00 - 3:30 Immunotherapy Dr. Karl Lewis PPT Slides Presentation

3:30-3:40 Environmental Scans Eric Taber

3:40 - 3:50 New Business Dr. Madeleine Kane Add your own calendar event to the CCC calendar- How To File ​

3:50 pm Partner Updates Share programs and events from your organization

, 2017 Quarterly Meeting January 26 ​2017 ​ Dates 2-4 pm ACS – Brooks Conference Center Zoom will be available

April 2017 TBD- Will likely be a 1-1.5 day symposium instead of Quarterly Meeting

July 27, 2017 12-2 pm Location TBD Zoom will be available

October 26, 2017 2-4 pm Location TBD Zoom will be available

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TASK FORCE UPDATES

**Meeting info may change. If you are not on the Task Force distribution list, be sure to contact the chair to confirm the meeting information**

BREAST CANCER TASK FORCE

Task Force Chairs Contact Info Meeting Date

th Breast Brandy bbrogan@projectangelh November 17 ​ 9:30-11am. ​ Cancer Task Brogan eart.org American Cancer Society, 2255 S Oneida Force St, Denver, CO

Breast Cancer Task Force Update

Next meeting is from 9:30-10am on November 17th. There will be an opportunity to network and connect with other members of the task force at the beginning of the meeting.

The Breast Cancer Task Force published an advertisement in the Colorado Nurses magazine that ​ ​ goes out to 72K ppl. They are hoping to bring awareness to everyone that IBC is also a concern and one that is less known. As knowledge is power they will be creating some slides about self-breast exams, screening info, connection information, and how to talk about breast cancer so individuals can include those in presentations they are already doing.

COLORECTAL CANCER TASK FORCE

Task Force Chairs Contact Info Meeting Date

Colorectal Jane Harris [email protected] November 10th, 7:30 am - 8:30 am ​ Cancer Task and [email protected] December 8th, 7:30 am - 8:30 am ​ Force Jackie Woods rg January 12, 2017 7:30 am - 8:30 am LOCATION: American Cancer Society, 2255 S Oneida St, Denver, CO

Colorectal Cancer Task Force Update

No update was submitted.

FAMILY HISTORY TASK FORCE

Task Force Chairs Contact Info Meeting Date

Family Emily Fields [email protected] Nov 21st, 8:00 - 9:30 am History Task facilitating s Dec19th, 8:00 - 9:30 am Force for now Jan 16, 2017, 8:00 - 9:30 am All via Zoom: https://zoom.us/j/9781446096

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Family History Task Force Update

We’re working on providing a list of resources on the CCC website. Do you have a particular family history risk assessment tool that you recommend we include? If so please email it to [email protected]

Do you know a genetic counselor who should be on this Task Force? Please send their information to [email protected]

FINANCIAL BARRIERS TASK FORCE

Task Force Chairs Contact Info Meeting Date

Financial Toni Panetta TPanetta@komencolora Oct 21, 12:00 - 1:30 pm Barriers Task and Tim do.org Nov 18, 12:00 - 1:30 pm Force Taravella ttaravella@senseofsecu Dec 16, 12:00 - 1:30 pm rity.org Jan 20, 2017, 12:00 - 1:30

Location: Colorado Foundation for Public Health and the Environment 1385 S. Colorado Blvd. Suite 622 Denver, CO 80222 Zoom remote link for all meetings: https://zoom.us/j/9781446096

Financial Barriers Task Force Update

The Financial Barriers Task Force held its second meeting on October 21. The group is working on updating the Action Plan, completing the Environmental Scan and the Resource Directory.

At the first meeting in August, participants were asked to review two documents shared by Toni Panetta - Patient Self-Advocacy Reference: https://drive.google.com/file/d/0BzprTC59c3WnR2M2cVh1M0FjNU9qUExYVjJGckdmSi02Z3lv/view?u sp=sharing

Checklist for Insurance Purchasing: https://drive.google.com/file/d/0BzprTC59c3WnTHNVQTdqeDhGbWROVHhSYmFELThrX2FYMVBr/vie w?usp=sharing

The Task Force is looking for a co-chair. Our next meeting is November 18.

HPV PREVENTION TASK FORCE

Task Force Chairs Contact Info Meeting Date

HPV Eric Taber [email protected] Nov 16, 10 am - 11:00 am - CDPHE - Prevention Building C, Room C1E Task Force https://zoom.us/j/539214139 Dec 8, 10 am - 11:00 am - CDPHE - Building C, Room C1E https://zoom.us/j/765832629 Jan 12, 2017, 10 am - 11:00 am - CDPHE - Building A, Snow Room

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https://zoom.us/j/638712777

HPV Task Force Update

At this month’s task force meeting, we finalized our ‘pitch’ of what the task force can offer and we’re reaching out to LPHAs and school nurses to offer our assistance and grow our membership base. We also initiated discussions with Denver Public Schools about their health education curriculum. Furthermore, we reviewed existing HPV educational materials (i.e. infographics and fact sheets) and we plan to coordinate with the Denver Metro Alliance for HPV Prevention to push out pieces of their communications campaign to a larger, statewide audience. Finally, we’ve identified community events where we can raise awareness about HPV vaccination, and this week we were at the Crucial Catch Day hosted by ACS and MCPN.

LUNG CANCER TASK FORCE

Task Force Chairs Contact Info Meeting Date

Lung Cancer Dr. Debby Dec 13, 5:30 pm Task Force Dyer and [email protected] Dr. Jim [email protected] Location: National Jewish Health, Room Fenton L111, 1400 Jackson Street, Denver CO 80206 Conference Call: 1-888-875-1833 Passcode: 93561200

Lung Cancer Task Force Update

Update will be provided at the meeting.

OVARIAN CANCER TASK FORCE

Task Force Chairs Contact Info Meeting Date

Ovarian Mary Phillips Cancer Task Force

Ovarian Cancer Task Force Update

No update was submitted.

PATIENT NAVIGATION TASK FORCE

Task Force Chairs Contact Info Meeting Date

Patient Morgan October 26, 2-3 pm Navigation Nestingen Task Force and Ron American Cancer Society, 2255 S Oneida Brady St, Denver, CO

Zoom remote link for all meetings: https://zoom.us/j/9781446096

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Patient Navigation Task Force Update

No update was submitted.

SKIN CANCER TASK FORCE

Task Force Chairs Contact Info Meeting Date

Skin Cancer Jessica Nov 8, 2 - 3 pm Task Force Mounessa and Dec 13, 2-3 pm Dr. Robert Denver VA, Neurology Conference Room, Dellavalle 1055 Clermont St. Room 6a-121, Denver CO 80220 Conference Call

Skin Cancer Task Force Update

● Our work was recently featured in the Denver Post ( http://www.denverpost.com/2016/10/10/colorado-sunscreen-melanoma/) and in the CDC ​ Success Story, "Specialized Photography Promotes Sun Safety in Colorado” (attached). ● Klein Buendel has received a mini-grant from the CDPHE to disseminate sun safety curriculum in 200 high altitude CO schools. ● Drs. Lori Crane and Nancy Asdigian from the Colorado School of Public Health and Dr. Dellavalle from the Department of Dermatology have begun a 2-year project funded by the CCPD to promote skin cancer prevention on 10 college campuses across Colorado. ● We have participated in a number of outreach events including the Summit , Bronco’s Wellness Fair, UPS Health Fair, Colorado Cancer and Wellness Conference. At these events we have provided sunscreen and educated participants on skin cancer prevention using our specialized cross-polarized light photography revealing sun damage. ● We will be involved in the upcoming Cancer Screening Provider Training.

SURVIVORSHIP TASK FORCE

Task Force Chairs Contact Info Meeting Date

Survivorship Cathy [email protected] Physical Health Work Group Task Force Bledsoe and m Nov 2, 9 am Sandy Dec 7, 9 am Priester [email protected] Jan 4, 2017 9 am g (Mental and Physical Location: Project Angel Heart ​ Health Workgroup 4950 Washington St., Denver, CO 80216 ​ contact) Remote connection: https://zoom.us/j/9781446096

Mental Health Work Group Nov 14, 1:00 pm Dec 12, 1:00 pm Jan 9, 2017, 1:00 pm

Location: Colorado Department of Public ​

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Health and Environment (CDPHE) 4300 Cherry Creek Drive South, Denver, CO 80246 Remote connection: https://zoom.us/j/9781446096

Transition Work Group - TBD Legislative/Reimbursement Work Group - TBD

Survivorship Task Force Meeting - TBD

Survivorship Task Force Update

Update will be provided at the meeting.

SCREENING COORDINATING COMMITTEE

Task Force Chairs Contact Info Meeting Date

Screening Ian Kahn and [email protected] Oct 18, 2-3 pm Coordinating Becky Selig [email protected] Nov 15, 2-3 pm Committee s Dec 20, 2-3 pm Jan 17, 2017, 2-3 pm

Location: American Cancer Society 2255 S Oneida St, Denver, CO

Conference: Call in: 323-484-8105 ​ Conference ID: 7534474

Screening Coordinating Committee Update

We are working to finalize the mission of this committee - key points that we'd like to include are: ● Core space to coordinate disparate rates of screening ● Synergize work that each task force is doing, avoiding overlap/duplication ● Identify areas of collaboration ● Share what all are currently doing on own (and across task forces), identify ways others can support and work on new projects together ● Collaborate on ways we can have a greater impact on policies and other systems level work that relates to screening

Projects/collaborations being discussed include:

● Early stages of looking into the feasibility of a state-wide screening registry ● Very early stages of discussing a public-facing screening website/assessment tool ○ Potentially start with a health assessment of sorts, would provide users with information on which screenings they are due for) ○ Expand to other functionalities like connecting to resources and specific patient needs

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● Potential 9HealthFair collaboration

Upcoming Provider Training for the primary care workforce - Nov. 4 - please share with your networks

● Cancer Screening session from 12:30-4:30pm. More information and to register here: http://tinyurl.com/NovProviderTraining

Action Needed: For remote attendees - Please fill in this survey at the conclusion of the meeting: ​ https://www.surveymonkey.com/r/CCCquarterlyfeedback

Websites: Colorado Cancer Coalition: http://www.coloradocancercoalition.org/ ​ Colorado Cancer Plan: https://www.colorado.gov/cancerplan ​

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Colorado Cancer Coalition Standing Committees

○ Resource Committee - Lead: Dr. Cathy Bradley ■ Develop resource plan and sponsorship packets to fund CCC activities. ■ Research grants and companies for potential funding opportunities. ■ On-going committee

○ Annual Symposium Committee - Lead: Dr. Tim Byers ■ Plan and execute the Annual Symposium. ■ Acquire speakers for the Symposium. ■ Acquire sponsors for the Symposium. ■ Primary time commitment: November - April

○ Colorado Cancer Fund: ■ Colorado Cancer Fund Communications - Lead: Cindi Vogt ● Develop communications plan to spread awareness of the check off fund. ● Acquire sponsors to cover advertising expenses. ● Primary time commitment: November - April ■ Colorado Cancer Fund Grantors: ● Review Cancer Fund applications and award competitive grants. ● Primary time commitment: Aug - Nov

○ Resource Directory Committee: ■ Review resources (as necessary). ■ Plan the development of the online resource directory. ■ Discuss the possibility of a printed directory. ■ On-going committee

○ Patient Advisory Committee: ■ A group of patients and survivors that are available to provide feedback as needs arise. ■ On-going. Ad hoc emails and meetings as necessary

○ Communications Committee: ■ Develop communications plan to broadcast Coalition messaging across the state. ■ On-going committee

If anyone is interested in joining a committee, please contact [email protected] ​ and [email protected] ​ Colorado Foundation for Public Health and the Environment Statement of Activities From 1/1/2016 Through 12/31/2016

CCC - Colorado Cancer Coalition (In Whole Numbers)

Total

Operating Revenue Contributions Contributions - Business 3,000 Contributions - Nonprofit/Foun 16,935 Total Contributions 19,935 Total Operating Revenue 19,935

Total Operating Revenue 19,935

Total Revenue 19,935

Operating Expenses Professional Fees Contractor Fees 3,055 Total Professional Fees 3,055 Non-Personnel Expenses Supplies 158 Total Non-Personnel Expenses 158 Conferences, Conventions & Meetings Conference/Meeting Food 52 Total Conferences, Conventions & 52 Meetings Miscellaneous Web Hosted Business Tools 341 Total Miscellaneous 341 Total Operating Expenses 3,607

Inter-Company Expenses Foundation Fiscal Service Fees 1,615 Total Inter-Company Expenses 1,615

Total Expenses (5,221)

Net Revenue Over Expenditures 14,714

Ending Fund Balance 14,714

Date: 10/26/2016, 11:12 AM Page: 1 10/25/2016

Immunotherapies Karl Lewis, MD Associate Professor University of Colorado Aurora, CO

Treatment Options for Cancer

• Surgery • Radiation • Systemic therapies: – – Hormonal therapy – Immune therapy – Targeted therapy

Treatment Options for Cancer

• Surgery Local therapies • Radiation • Systemic therapies: – Chemotherapy – Hormonal therapy – Immune therapy – Targeted therapy

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Systemic Therapies

• Chemotherapy: chemicals given to poison growing and dividing cells (cytotoxic)

Chabner BA, Roberts TG. Nat Rev Cancer. 2005;5:65-72.

Systemic Therapies (cont.)

• Hormonal therapy: some (breast, prostate) are sensitive to hormones – Blocking or changing hormone balance can lead to cancer cell death.

Tamoxifen Leuprolide

Systemic Therapies (cont.)

• Targeted therapies: – Proof of concept: CML results from very specific chromosomal translocation. – 2001: approval of imatinib based on work from Brian Druker at OHSU

"There is no question that we can defeat cancer. What it requires is knowledge. When we understand what is broken, we can fix it." ‐ Brian Druker, M.D., Director, OHSU Knight Cancer Institute

CML = chronic myelogenous leukemia

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Systemic Therapies (cont.)

• Immunotherapy: a treatment that uses the body’s own immune system to help fight cancer.

Immunology Terms

• Antigen: substance that induces an immune response in the body • Antibody: a circulating protein that binds to a specific antigen • Lymph node: small structures that contain immune cells and filter lymphatic fluid • Cytokines: secreted substances of immune cells that have an effect on other cells (interferon, interleukin, etc.)

Major Players in Cancer Immunology • CD8+ cytotoxic T cells (Tc): cells that kill cancer cells, cells that are infected (e.g., with viruses), or cells that are damaged in other ways. • CD4+ helper T cells (Th): help the activity of other immune cells by releasing cytokines (e.g., stimulate B cell antibody secretion). • Dendritic cells = antigen presenting cells (APC): process antigen and present it on the cell surface to T cells. • Regulatory T cells (Treg): immunosuppressive

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Cancer Immunity Cycle

4 T-cell trafficking to tumours (CTLs) 3 Priming & activation (APCs and T cells) 5 T-cell infiltration into tumours (CTLs, endothelial cells)

blood vessel 2 Antigen presentation lymph node (DCs and other APCs) 6 T-cell recognition of cancer cells

tumour

1 Antigen release 7 Killing of cancer cells (cancer cell death)

Chen DS, Mellman I. Immunity. 2013;39:1–10.

ImmunotherapyImmunotherapy Milestones Milestones

Melero I, et al. Nat Rev Clin Oncol. 2014;11:509–524.

William B. Coley

• 1890’s: Injected first pt with streptococcal organisms based on reports of cancer regression in pts developing infections • Coley’s Toxin: heat-killed Streptococcus and Serratia sp. • Injected over 1,000 pts throughout his career • Significant criticism based on inconsistent and non- reproducible results.

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Regression of Primary Melanoma

Vitiligo of Metastatic Melanoma

High-dose IL-2 in Metastatic Survival for the whole study Melanomapopulation (270 patients) treated with high-dose IL2

1.0 Survival for the whole study population (270 patients) treatedMedian with high-dose survival 11.4 IL-2 months 0.8

0.6

0.4 Probability of Survival ofProbability 0.2

0.0 0 12 24 36 48 60 72 84 96 108 120 132 Months

Atkins MB, et al. J Clin Oncol. 1999;17:2105.

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PET Scans of Melanoma Patient Treated with IL-2

Immune Cytokines: IL-2

• Proof that immune system can control/eliminate cancer

• Unable to select patients who will respond

• Associated with high toxicity

Monoclonal Antibodies as Cancer Therapy • Antibodies that are designed to specifically target certain antigens, particularly antigens that are found on cancer cells • Generally not naturally occurring antibodies • Chimeric antibodies: consist of both mouse and human elements

Image retrieved from: http://www.cancerresearchuk.org/file/53146

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Tumor-associated Antigens Targeted by Therapeutic Monoclonal Antibodies

Antigen Examples of Examples of therapeutic mAbs Tumour types expressing category antigens raised against these targets antigen Haematopoietic CD20 Non-Hodgkin’s lymphoma differentiation antigens and Lymphoma CD30 Hodgkin’s lymphoma DC33 Acute myelogenous leukemia CD52 Chronic lymphocytic leukemia Glycoproteins EpCAM IGN101 and Epithelial tumors (breast, colon and lung) expressed by solid tumors CEA Breast, colon and lung tumors gpA33 huA33 Colorectal carcinoma Mucins and Breast, colon, lung and ovarian tumors TAG-72 CC49 () Breast, colon and lung tumors CAIX cG250 Renal cell carcinoma PSMA J591 Prostate carcinoma Folate-binding MOv18 and MORAb-003 () Ovarian tumors protein Glycolipids Gangliosides (such , ch14.18 and KW-2871 Neuroectodermal tumors and some epithelial as GD2, GD3 and tumors GM2)

Carbohydrates Le hu3S193 and IgN311 Breast, colon, lung and prostate tumors

Scott AM, Wolchok JD, Old LJ, et al. Nat Rev Cancer. 2012;12:278-287.

Tumor-associated Antigens Targeted by Therapeutic Monoclonal Antibodies

Antigen Examples of Examples of therapeutic Tumour types expressing antigen category antigens mAbs raised against these targets Targets of anti- VEGF Tumor vasculature angiogenic mAbs VEGFR IM-2C6 and CDP791 Epithelium-derived solid tumors Integrin αVß3 Tumor vasculature Integrin α5ß1 Volociximab Tumor vasculature Growth and EGFR , , Glioma, lung, breast, colon, and head and neck tumors differentiation and 806 signaling ERBB2 and Breast, colon, lung, ovarian and prostate tumors ERBB3 MM-121 Breast, colon, lung, ovarian and prostate tumors MET AMG 102, METMAB and SCH Breast, ovary, and lung tumors 900105 IGF1R AVE1642, IMC-A12, MK-0646, Glioma, lung, breast, head and neck, prostate and R1507 and CP 751871 thyroid cancer EPHA3 KB004 and IIIA4 Lung, kidney and colon tumors, melanoma, glioma and hematological malignancies TRAILR1 (HGS-ETR1) Colon, lung and pancreas tumors and hematological malignancies TRAILR2 HGS-ETR2 and CS-1008 RANKL Denosumab Prostate cancer and bone metastases Stromal and FAP 3F8, ch14.18 and KW-2871 Neuroectodermal tumors and some epithelial tumors extracellular matrix Tenascin 81C6 Glioma, breast and prostate tumors antigens Scott AM, Wolchok JD, Old LJ, et al. Nat Rev Cancer. 2012;12:278-287.

FDA-approved Monoclonal Antibodies and Their Mechanisms of Action

Antibody Target FDA-approved indication Mechanisms of action

Naked antibodies: solid malignancies Trastuzumab: ERBB2 ERBB2-positive breast cancer, as a single agent or in Inhibition of ERBB2 signaling humanized IgG1 combination with chemotherapy for adjuvant or palliative and ADCC treatment ERBB2-positive gastric or gastro-esophageal junction carcinoma as first-line treatment in combination with cisplatin and capecitabine or 5-fluorouracil Bevacizumab: VEGF For first-line and second-line treatment of metastatic colon Inhibition of VEGF signaling humanized IgG1 cancer, in conjunction with 5-fluorouracil-based chemotherapy; for first-line treatment of advanced NSCLC, in combination with carboplatin and paclitaxel, in patients who have not yet received chemotherapy; as a single agent in adult patients with glioblastoma whose tumor has progressed after initial treatment; and in conjunction with IFNα to treat metastatic kidney cancer Cetuximab: chimeric EGFR In combination with radiation therapy for the initial treatment Inhibition of EGFR signaling human-murine IgG1 of locally or regionally advanced SCCHN; as a single agent and ADCC for patients with SCCHN for whom prior platinum-based therapy has failed; and palliative treatment of pretreated metastatic EGFR-positive colorectal cancer Panitumumab: human EGFR As a single agent for the treatment of pretreated EGFR- Inhibition of EGFR signaling IgG2 expressing, metastatic colorectal carcinoma : IgG1 CTLA4 For the treatment of unresectable or metastatic melanoma Inhibition of CTLA4 signaling

Scott AM, Wolchok JD, Old LJ, et al. Nat Rev Cancer. 2012;12:278-287.

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FDA-approved Monoclonal Antibodies and Their Mechanisms of Action

Antibody Target FDA-approved indication Mechanisms of action

Naked antibodies: hematological malignancies Rituximab: chimeric CD20 For the treatment of CD20-positive B cell NHL and CLL, and ADCC, direct induction of human-murine IgG1 for maintenance therapy for untreated follicular CD20- apoptosis and CDC positive NHL

Alemtuzumab: CD52 As a single agent for the treatment of B cell chronic Direct induction of apoptosis humanized IgG1 lymphocytic leukemia and CDC : human CD20 Treatment of patients with CLL refractory to fludarabine and ADCC and CDC IgG1 alemtuzumab Conjugated antibodies: hematological malignancies Gemtuzumab CD33 For the treatment of patients with CD33-positive acute Delivery of toxic payload, ozogamicin: myeloid leukemia in first relapse who are 60 years of age or calicheamicin toxin humanized IgG4 older and who are not considered candidates for other cytotoxic chemotherapy; withdrawn from use in June 2010 Brentuximab vedotin: CD30 Fr the treatment of relapsed or refractory Hodgkin’s Delivery of toxic payload, chimeric IgG1 lymphoma and systemic anaplastic lymphoma auristatin toxin 90Y-labeled CD20 Treatment of relapsed or refractory, low-grade or follicular B Delivery of the radioisotope ibitumomab tiuxetan: cell NHL 90Y murine IgG1 Previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy 131I-labeled CD20 Treatment of patients with CD20 antigen-expressing Delivery of the radioisotope tositumomab: murine relapsed or refractory, low-grade, follicular or transformed 131I, ADCC and direct IgG2 NHL induction of apoptosis Scott AM, Wolchok JD, Old LJ, et al. Nat Rev Cancer. 2012;12:278-287.

Rituximab

Fc Heavy-chain (gamma) constant region

Light-chain (kappa) constant region Fab Light-chain (anti-CD20) variable region

Heavy-chain (anti-CD20) variable region

Figure above -

Rituximab is a chimeric antibody of the immunoglobulin G1 kappa type with murine anti-CD20 variable-sequence regions (filled areas) and human constant-sequence regions (open areas).

Wood AM. Am J Health Syst Pharm. 2001;58(3).

Rituximab Added to Standard Chemotherapy Addition of rituximab to standard chemotherapy improved the overall and event-free survival of patients with lymphoma

Fu K, et al. JCO. 2008;26:4587-4594.

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Vaccines

• A preparation that is administered to produce or artificially increase immunity to a particular disease

• Have been tested for several decades, but advances in this field have been slower than for other forms of immunotherapy

• Therapeutic and preventative

Preventative Vaccines

• Some cancers are caused by viruses. Vaccines that protect against infections with these viruses may prevent cancer. • HPV: cervical, anal, throat • HBV: liver cancer

Therapeutic Vaccines

• Instead of preventing disease, they are meant to get the immune system to attack a disease that already exists • Made up of cancer cells, parts of cells, or pure antigens that try to get the immune system to attack cells with those specific antigens • Many have been or are under investigation • Overall, very disappointing results • Only one therapy approved by the FDA to treat advanced cancer to date

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Sipuleucel-T for Advanced Prostate Cancer

Figure: The diagram illustrates the two steps involved in sipuleucel-T therapy: (1) harvesting the patient’s dendritic cells and then pulsing these ex vivo with a recombinant made of prostatic acid phosphatase (PAP) and granulocyte- macrophage colon- stimulating factor (GM- CSF); and (2) infusing the cultured cells into the patient, where the PAP-GM-CSF-loaded antigen-presenting cells induce the proliferation of T-cells that recognize and target prostate tumor cells.

Garcia JA, Dreicer R. 2011. Diagn Imaging. 2011;1-11.

D9902B – IMPACT

P R R A Placebo q2wks Eligible for O N x 3 Sipuleucel-Ta G  mCRPC D  No Visceral R O Mets E M  N = 512 S I Sipuleucel-T S Physician’s Z q2wks x 3 I Discretion E O N  Patients: Asymptomatic or minimally symptomatic mCRPC  Primary end point: OS  Secondary end point: TTP aPrepared from cryo-preserved lymphocytes. IMPACT = immunotherapy prostate adenocarcinoma treatment; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; TTP = time to progression. Kantoff CS, et al. N Engl J Med. 2010;363:411-422.

IMPACT OS: Primary Endpoint ITT Population

Sipuleucel-T: First therapeutic cellular immunotherapy to demonstrate effectiveness in Phase III clinical trials; first FDA approved therapeutic cancer vaccine

100 • p = .032 (Cox model) HR = 0.775 [95% CI 80 0.614, 0.979]

• Median Survival Benefit 60 = 4.1 mos

Sipuleucel-T 40 • Sipuleucel-T (n = 341) Median Survival = 25.8 mos 20 Placebo

Probability of Survival (%) Survival of Probability • Placebo (n = 171) 0 Median Survival = 21.7 0 12 24 36 48 60 72 mos Months since Randomization

ITT = intent-to-treat; HR = hazard ratio; CI = confidence interval Kantoff CS, et al. N Engl J Med. 2010;363:411-422.

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Conclusions: Vaccines

• Therapeutic vaccines have been extensively studied with limited efficacy so far – Sipuleucel-T is the only FDA-approved vaccine • Preventative vaccines for certain cancers are effective

TVEC

• Talimogene laherparepvec (TVEC) – an oncolytic virus encoding human GM-CSF approved for melanoma

TVEC

Directly attacks tumour cells1,2 Induces a systemic anti-tumour immune response1,2

Death of distant tumour cells

GM-CSF = granulocyte-macrophage colony-stimulating factor 1. Kaufman HL, et al. J Immunother Cancer. 2014;2:11. 2. Drake CG, et al. Nat Rev Clin Oncol. 2014;11:24–37.

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Durable Response Rates With TVEC in Advanced Melanoma

Stages IIIB, IIIC, IVM1a2 Stages IVM1b, M1c2

Taken from Senzer 20091

First-line treatment Second-line or greater

1. Senzer N, et al. J Clin Oncol. 2009;27:5763–5771. 2. Andtbacka R, et al. J Clin Oncol. 2015;33(25):2780– 2788. 3. NCT02263508. Available at: https://clinicaltrials.gov/ct2/show/NCT02263508. Accessed May 2016.

Checkpoint Inhibitors

• Our immune system has many mechanisms to shut itself off to prevent it from recognizing “self”

• We don’t want an overactive immune system – Autoimmunity

Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy

Ribas A. N Engl J Med. 2012;366:2517-2519

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Ipilimumab with Metastatic Melanoma Phase III Trial of Ipilimumab ± gp100 Vaccine Vs. gp100 Vaccine Alone: MDX010-20 Ipilimumab + gp100 R (n = 403) A Pretreated N Metastatic D Ipilimumab + Placebo Melanoma O (n = 137) (N = 676) M I gp100 + Placebo Z (n = 136) E • Primary end point: OS • Secondary end points: ORR, DOR, PFS

OS = overall survival; ORR = overall response rater; DOR = duration of response; gp100 = glycoprotein 100; PFS = progression-free survival Hodi FS, et al. N Engl J Med. 2010;363(8):711-723.

Kaplan-Meier Analysis of Survival

Comparison HR p-value Arms A vs C 0.68 0.0004 Arms B vs C 0.66 0.0026

A = Ipilimumab + gp100 B = Ipilimumab alone C = gp100 alone

B A C

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

Ipilimumab Patterns of Response

Week 12: Week 14: Screening Swelling & progression Improved

“mobile”

Week 16: Week 72: Week 108: Continued improvement Complete remission Complete remission

(Memory)

Maggon. 2011. Available at: http://www.slideshare.net/MelanomaResearchFoundation/2014-seattle-patient- symposium-slide-deck. Accessed August 26, 2016.

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Pooled OS Analysis Including EAP Data: 4846 Patients

1.0 0.9 Median OS (95% CI): 9.5 (9.0–10.0) 0.8

0.7

0.6

0.5 3-year OS Rate (95% CI): 21% (20–22%)

0.4

0.3 Proportion Alive

0.2

0.1 Ipilimumab CENSORED 0.0

0 1224364860728496108120 Months Patients at Risk Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0 EAP = expanded access treatment protocol Schadendorf D, et al. J Clin Oncol. 2015;33(17):1889-1894.

OS Relative to Historical Data

1.0 1.0 Phase II Ipilimumab Phase III Ipilimumab Predicted Survival (Kom Model) Predicted Survival (Kom Model)

0.8 0.8

ility 0.6 ility 0.6

0.4 0.4 Survival Probab Survival Probab Survival

0.2 0.2

0.0 0.0

0 20 40 60 80 100 120 0 20 40 60 Time (months) Time (months) • Historical controls – Phase II: 1278 patients in 42 cooperative group trials from 1975 to 20051 – Phase III: 3739 patients in 10 trials from 1999 to 2011 1. Korn EL, et al. J Clin Oncol. 2008;26(4):527-34.

BlockadeBlockade of PD-1 or CTLA-4 of PD-1Signaling in or Tumor CTL Immunotherapy.A-4 Signaling in Tumor Immunotherapy

Ribas A. N Engl J Med. 2012;366:2517-2519.

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PD-1 Antibodies

• and were both first approved to treat metastatic melanoma

• Response rates, in general, higher than ipilimumab

• Toxicities, in general, less than ipilimumab

• MAJOR BREAKTHROUGH in immunotherapy and cancer in general!!!!

Pembrolizumab vs Ipilimumab in Treatment of Metastatic Melanoma

RR 33.7%

RR 32.9%

RR 11.9%

Robert C et al. N Engl J Med. 2015;372:2521-2532.

Pembrolizumab vs Ipilimumab in Treatment of Metastatic Melanoma

100 100 Pembrolizumab, Q3W 90 90 Pembrolizumab, Q2W 80 80 70 70 Pembrolizumab, Q2W 60 60 50 50 Ipilimumab 40 40 30 30 Pembrolizumab, Q3W

20 (%) survival Overall 20

10 Ipilimumab 10 Progression-free survival Progression-free survival (%) 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 16 18 Months Months 6-month PFS: 12-month OS: 2 wk: 47.3% 2 wk: 74.1% 3 wk: 46.4% 3 wk: 68.4% Ipi: 26.5% Ipi: 58.2%

Robert C et al. N Engl J Med. 2015;372:2521-2532.

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Studies of PD-1 Antibodies

• Garon EB, et al. Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl J Med. 2015;372:2018-2028. • Seiwert TY, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicenter, phase 1b trial. Lancet Oncol. 2016;17(7):956-965. • Borghaei H, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-1639. • Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-13. • Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-319.

Studies of PD-1 Antibodies (cont.)

Larkin J et al. N Engl J Med. 2015;373:23-34.

Progression-Free Survival (Intent- to-Treat Population)

NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) 100 Median PFS, months (95% 11.5 (8.9–16.7) 6.9 (4.3–9.5) 2.9 (2.8–3.4) CI) 90 HR (99.5% CI) vs. IPI 0.42 (0.31–0.57)* 0.55 (0.43–0.76)* -- 80 HR (95% CI) vs. NIVO 0.76 (0.60– -- -- 70 0.92)**

60 *Stratified log-rank P<0.00001 vs. IPI **Exploratory endpoint 49% 50 46%

40 42%

Percentage of PFS Percentage of 39% 30 Progression-free Survival (%) Progression-free Survival

20 NIVO+IPI NIVO 18% 10 14% IPI 0 0 3 6 9 12 15 1821 24 27 PFS per Investigator (months)

Number of patients at risk: Nivolumab + Ipilimumab 314 219 174 156 133 126 103 48 8 0 Nivolumab 316 177 148 127 114 104 94 46 8 0 Ipilimumab 315 137 78 58 46 40 25 15 3 0

Larkin J et al. N Engl J Med. 2015;373:23-34.

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Ipilimumab + Nivolumab Combination in Melanoma

Larkin J et al. N Engl J Med. 2015;373:23-34.

Toxicities of Checkpoint Inhibitors

• Toxicity is a direct result of mechanism of action: alter self-tolerance • Particular side effect is direct result of organ/tissue being attacked by the immune system:

– GI

– Skin

– Endocrine system

– Kidney

– Lungs

– Etc. • Treatment of toxicity (moderate/severe) is immune suppression • This IS NOT chemotherapy-related diarrhea!!

GI = gastrointestinal

Conclusions: Checkpoint Inhibitors

• Checkpoint inhibitors are an effective treatment for melanoma, and probably other cancers, resulting in durable responses in some patients.

• Toxicity can be great – ipilimumab.

• Newer agents (PD-1 antibodies) result in larger numbers of patients benefiting.

• Combinations of agents (Ipi + PD-1) appear to result in greater benefit still.

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Different Drugs Target Distinct Steps of the Cancer Immune Cycle

4 T-cell trafficking to tumours (CTLs) 3 Priming & activation (APCs and T cells) CD27 5 T cell infiltration into TVEC tumours (CTLs, endothelial cells) Tumour-infiltrating blood vessel 2 lymphocytes Antigen presentation lymph node (DCs and other APCs) Anti-CD40 mAb 6 T cell recognition of cancer cells Anti-PD-L1 mAb

tumour

1 Antigen release 7 Killing of cancer cells (cancer cell death) IDO inhibitor TVEC Anti-OX40 Anti-CSF-1R

Chen DS, Mellman I. Immunity. 2013;39:1-10.

Conclusions: Immunotherapy

• Many ways to attack/treat cancer by manipulating the immune system.

• Studies have brought variable success.

• Vaccines have limited therapeutic benefit to date.

• Cytokines and checkpoint inhibitors can result in long- term, durable responses (mainly in melanoma but now in many other cancers as well).

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EVALUATION OF THE COLORADO CANCER COALITION QUARTERLY MEETING Thank you for attending! Please complete our brief evaluation. Date ______

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2. What was most valuable about this meeting to you or your organization?

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4. How can we make quarterly Coalition meetings more useful to you?

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