Innovations in Cancer Treatment

Innovations in Cancer Treatment
Idaho Society of Health-Systems Pharmacists Innovations in Cancer Treatment Stephanie Magdanz, PharmD, BCOP Oncology Clinical Pharmacist Boise VA Medical Center March 6, 2016

Disclosures Stephanie Magdanz, PharmD, BCOP reports having no financial or advisory relationships with corporate organizations Often wish I did

Learning Objectives Recognize the disadvantages & challenges of traditional cancer therapies. Explain how monoclonal antibodies stimulate the immune system to attack cancer cells. Summarize the process of CAR-T therapy. Describe how viruses can be used to treat cancer.

Cancer Statistics In the U.S., 1 of every 2 men and 1 of every 3 women in will receive a cancer diagnosis in their lifetime Cancer is the #2 cause of death in the United States Projected to surpass heart disease as #1 in the next decade Cancer is the #1 cause of death in Idaho Cancer is the #1 cause of death by disease in children Every 3 minutes, somewhere in the world, a child is diagnosed with cancer There are now >14 million cancer survivors in the U.S. 5-year survival for all cancers is >68% ( ) up from 49% in the late 1970s The FDA approved 18 new cancer drugs in 2015 compared to 6 in 2010 Currently 800 ongoing clinical trials for new cancer immunotherapy drugs; only 5% of cancer patients participate in clinical trials Cancer spending is roughly 5% of the total spent on medical care in the U.S in general 1. Incidence expected to increase sharply over the coming years as the US population ages 2. Two million more than in 2008 2. Death rates fell for the first time in the 1990s and continue to decline Sweeney N, et al. Boston Healthcare. May 2015.

Cancer Statistics

History of Cancer Treatment
1550 BC – Egyptian papyrus written by Imhotep is the first documentation of cancer 460 BC – Hippocrates “names” cancer using the terms carcinos & carcinoma from the Greek word for crab 160 AD – Medical conditions were explained by the four humors (blood, black bile, yellow bile, white bile) 1775 – British surgeon Percival Pott reported increased scrotum cancer among chimney sweeps 1846/1865 – Anesthesia & antiseptic (carbolic acid) discovered 1878 – Paul Erlich discovers the principle of what will later be known as chemotherapy 1895 – Discovery of x-ray & experiments in treating cancer 1937 – National Cancer Institute Act signed by President Roosevelt 1. Evidence also found in hieroglyphics and Osteosarcoma in Egyptian mummies Hippocrates is often considered the father of Western medicine. Inspired by the characteristics of a tumor Imbalance or surplus of black bile was thought to be the origin of cancer Allowed new surgeries to treat cancer A chemical he developed to treat syphilis in 1909 History of Cancer Timeline The History of Cancer

1941 – WWII soldiers exposed to mustard gas found to have toxic changes to bone marrow Led to development of alkylating agents in 1943 at Yale 1945 – American Cancer Society founded 1948 – Sidney Farber, the “father of chemotherapy” used aminopterin (methotrexate) to treat leukemia patients 1952 – Screening being done using pap smear, colonoscopy & mammography 1955 – Marlboro Man ad campaign; sales up 5000% over 8 months 1956 – First bone marrow transplant done in leukemia patient 1957 – US Surgeon General report that cigarette smoking is causative factor in lung cancer 1969/1971 – War on Cancer; Nixon signs National Cancer Act 1976 – Mammogram Screening Trial results in 20% reduction in deaths for women >55 1. Didn’t know how to spell cigarette History of Cancer Timeline The History of Cancer

1982 – High-dose chemo + autologous HSCT in solid tumors; found to have no benefit by late 1990s 1992 – Breast cancer HER-2 gene identified 1999 – Imatinib (Gleevec®) trial – launch of targeted therapies 2003 – Human Genome Project completed – map of entire sequence of human DNA 2006 – Cancer Genome Atlas – gene sequencing of tumors 2010 – President’s Cancer Panel – increased research 2011 – Emphasis on Oncology immunotherapy research (ie: ipilimumab for malignant melanoma) 2015 – President Obama’s “Moonshot to Cure Cancer” – calls for expanded funding & screening, increased access to clinical trials, insurance coverage of gene testing, decreased prescription drug prices, & sharing of information Cancer link to changes in genes is now well understood Approved in 2001, first oral targeted drug, stopped growth of cancer cells, one of most successful trials in history of cancer Crucial for cancer researchers to explore genomic path of cancer To improve detection, treatment and prevention. Can juxtapose normal genome with cancer’s abnormal genome. At least 200 forms of cancer; each caused by errors in DNA Immunotherapy is fastest growing pharmaceutical sector (cancer & ID) Comparison to JFK’s call for US to put astronaut on the moon. Cose of new course of cancer therapy has increased in past decade from $10,000 to $100,000. Pharmaceutical companies protect research results for competetive reasons Take home message – we’ve learned more about cancer in the last 2 decades than at any other time in history History of Cancer Timeline The History of Cancer “Moonshot” article

Cancer Treatment: Drawbacks & Challenges
Surgery, radiation & chemotherapy Not all patients who need the treatment are eligible Considerable adverse effects including death, pain, infections, heart failure, fatigue, nausea/vomiting, etc Long-term sequelae – heart failure, pulmonary, secondary cancers Some cancer cells may survive causing progression or recurrence Tumor resistance Immune system has a critical role in cancer pathogenesis (ie: immunocompromised patients) Solid organ transplant – 2-fold increase in solid tumors & 20-fold increase in skin cancer, lymphoma & sarcomas HIV – 40% of AIDS patients develop cancer Tumors consist mainly of normal tissue components (self) 1. Residual cells can settle in & start to multiply over time 2. Why do some patients recur and some don’t – immune system!! Cancer immunotherapy BiTE antibodies

Cancer Treatment: Drawbacks & Challenges
Tumor resistance (cont.) Immune system is trained to avoid attacking itself Cytotoxic T lymphocytes (CTLs) recognize tumor antigens, bind & cause tumor cell lysis Problem – tumors can evade T cell recognition (escape phase) Immune system exhaustion Tumor growth is too fast for immune system to keep up Checkpoints on the T cell (CTLA-4 & PD-1) are upregulated causing the T cell to turn off Tumors can secrete immunosuppressive cytokines Solution – the new era of cancer treatment Encourage immune cells that recognize tumor Help immune system track down wandering cancer cells & destroy them Develop tumor specific Ab’s outside the body & inject them into patients Cancer is a crafty disease & finds ways to get around our treatments That time is NOW! Cancer immunotherapy BiTE antibodies

Cancer Treatment: A New Era
Cytokines – T cell growth factors that stimulate immune response (ie: interferons, interleukins) Allogeneic HSCT – tumor cells eliminated through high-dose chemotherapy followed by graft-versus-tumor effect Monoclonal Antibodies – direct or indirect immune response Rituximab – immune-mediated cytotoxic response Trastuzumab & cetuximab – block signal pathways needed for cell growth Bevacizumab – block angiogenesis needed for oxygen & nutrients Brentuximab vedotin – antibody drug conjugate (ADC) combining a monoclonal Ab with cyctotoxic drug Tositumomab 131I – antibody combined with radioactive particle Oral molecular target drugs (aka tyrosine kinase inhibitors, signal transduction inhibitors, “nibs”) Old school treatments Cytokines – not specific enough, horrible SE Rituxan – makes cancer cell more visible to immune system Herc – tumor cells have extra GF receptors to grow faster Brentux – trojan horse Tositum – delivers radiation directly to the cell NEED DIAGRAM EXAMPLES Cancer immunotherapy

Small Molecule TKIs/STIs
Trastuzumab Monoclonal Antibodies Bevacizumab Cetuximab Panitumumab Tipifarnib Lonafarnib Erlotinib Imatinib Lapatinib Sorafenib Small Molecule TKIs/STIs mTOR Hudis CA. NEJM 2007;357(1):41

LoRusso P M et al. Clin Cancer Res 2011;17:6437-6447

Cancer Treatment: A New Era
Autologous cellular immunotherapy – activated APCs are reinfused into patient to direct immune cells vs tumor cell (ie: sipuleucel-T) Immune checkpoint inhibitors – “release the brakes” on the immune system (ie: ipilimumab, nivolumab, pembrolizumab) CAR-T therapy – chimeric antigen receptor (CAR) T cells Immunovirus – therapeutic cancer vaccine Future directions – BiTE antibodies, DNA methylation signature, TMEM score, magic wands, IDH2 blockers, proteomics, intraoperative radiation, CRISP-R technology Cancer immunotherapy

Patient Case #1: PD-1 Inhibitor
ED 33yo male with Hodgkins Lymphoma Apr 2011: standard chemo w/ ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) x6 cycles 2nd line chemo: GDP (gemcitabine, dexamethasone, cisplatin) 2012: autologous stem cell transplant → recurrence Salvage chemo: brentuximab vedotin (Adcetris®) Salvage chemo: GDP, MOPP (mechlorethamine, vincristine, procarbazine, prednisone), bendamustine Dec 2014: allogeneic stem cell transplant → recurrence Now what??? Mention it’s an immune checkpoint inhibitor

Patient Case #2: CAR-T Therapy
JA 3yo male with Acute Lymphocytic Leukemia (ALL) 2013 – diagnosed at age 18 months 2 year battle chemotherapy → relapsed twice Allogeneic stem cell transplant → relapse Out of treatment options other than hospice Now what??? Strongagainstcancer.org

Patient Case #3: Immunovirus
SL 20yo female with tennis ball sized GBM (glioblastoma multiforme) brain tumor 2011 – surgery; 98% removed Radiation & chemotherapy (temozolamide) Recurrence 2012 → 1st patient on Phase I Polio immunovirus trial at Duke University Treatment began in May → tumor is larger by June What happened next??? What do these 3 patients have in common?? 60 Minutes: Killing Cancer Part 1 & 2, Mar 29, Available at

Immunotherapy: Checkpoint inhibitors
Immune system relies on multiple checkpoints to avoid over activation on healthy cells Tumor cells hijack these checkpoints to escape detection CTLA-4 & PD-1 are upregulated on T cell surface in some cancers PD-L1 can be expressed on tumor cells endogenously or induced by association with T cells PD-1:PD-L1 interaction results in T cell suppression (anergy, exhaustion, death) Not going to talk about CTLA-4 – not shown to be effective in lung or prostate studies & not studied for renal cell Atkins MB et al. Clinical Care Options slideset 2014.

NIVOLUMAB PEMBROLIZUMAB
IPILIMUMAB NIVOLUMAB PEMBROLIZUMAB Drake CG et al. Nat Rev Clin Onc. 2014;11:24-37.

Immunotherapy: Checkpoint inhibitors
In melanoma, renal cell, & other tumors, PD-L1 expression is associated with more aggressive disease Inhibiting CTLA-4 & PD-1 can “release the brakes” Checkpoint inhibitors don’t attack the tumor, they set the T cells straight Activity powerful enough to work in the CNS – T cells go everywhere Melanoma patients – on MRI, brain mets are surrounded by tons of T cells Atkins MB et al. Clinical Care Options slideset 2014.

Immunotherapy: Checkpoint blockade
Priming phase (lymph node) Effector phase (peripheral tissue) T-cell migration Dendritic cell Cancer cell T cell T cell Dendritic cell T cell MHC TCR B7 CD28 CTA-4 MHC TCR MHC MHC CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; TCR, T cell receptor. CD28 T cell PD-1 PD-1 Cancer cell PD-L1 PD-L1 B7 CTLA-4 Ribas A. N Engl J Med. 2012;366:

Immunotherapy: PD-1 inhibitors
Nivolumab (Opdivo®) – FDA approval Melanoma – unresectable or metastatic; single agent or combination with ipilimumab NSCLC – metastatic; with progression on or after platinum-based chemotherapy and EGFR or ALK therapy if EGFR or ALK positive Renal Cell – advanced disease who have received 1 or 2 prior therapies Summary – ORR in patients with advanced NSCLC, melanoma, renal cell carcinoma 65 of 306 patients had ORR (CR or PR) 30 of those 65 (46%) had response evident at first tumor eval (8wks) 42 of those 65 (65%) had response lasting >1yr 35 of those 65 (54%) had response ongoing at time of data analysis Response persisted off the drug Define CR & PR Nivolumab pkg insert Atkins MB et al. Clinical Care Options slideset 2014.

Nivolumab in Hodgkin’s Lymphoma Phase I – 23 patients who failed >3 previous regimens including brentuximab vedotin and HSCT ORR 87% (20/23 patients) w/ CR in 4 (17%) with 40-wk follow-up No life threatening toxicities or treatment deaths Activity in breast, ovarian, colon, bladder, hepatic, gastric, head & neck, pancreatic, GBM, lymphomas, & many others Multiple combinations being studied (ie: with vaccines & with other targeted drugs) Want to use earlier – prevent short & long term toxic effects with chemo & HSCT Nivolumab package insert Mulcahy N. Medscape Abstr 289 & 290.

Pembrolizumab (Keytruda®) – FDA approval Melanoma – unresectable or metastatic NSCLC – metastatic; with progression on or after platinum-based chemotherapy and EGFR or ALK therapy if EGFR or ALK positive Activity in SCLC, esophageal, breast, ovarian, head & neck, pancreatic, lymphomas, & many others Former President Jimmy Carter Melanoma diagnosed August 2015 – liver & brain mets Surgery, radiation, pembrolizumab Currently no evidence of disease including brain mets Multiple combinations being studied (ie: vaccines & parp inhibitors) Now have to wait and see if melanoma returns PD-L1 is an unreliable biomarker Assays are difficult & imperfect High false negative rate – tumor heterogeneity Archived tissue different than recent biopsy May be less relevant for combination therpies Pembrolizumab pkg insert Mulcahy N. Medscape Abstr 289 & 290, Mills D

Disease can get worse before it gets better Four distinct response patterns associated with favorable overall survival (OS) Response in baseline lesions Stable disease with slow decline in tumor volume Response following an initial increase in tumor volume Response following appearance of new lesions Infiltration of patient immune cells can cause an initial increase in tumor volume or appearance of new lesions on imaging scans (know as pseudoprogression) Need 8-12 doses to accurately evaluate patient response Atkins MB et al. Clinical Care Options slideset 2014.

Immune-mediated toxicity Overall, gentler than CTLA-4 inhibitors Occasional (5-20%) Fatigue Rash – maculopapular, pruritis Diarrhea/colitis – initiate steroids early, taper slowly Hepatitis/liver enzyme abnormalities Infusion reactions Endocrinopathies – thyroid, adrenal, hypophysitis Infrequent (<5%) Pneumonitis Grade 3 or 4 toxicities are uncommon Atkins MB et al. Clinical Care Options slideset 2014

CAR-T Therapy Chimeric antigen receptor (CAR) T cell therapy
T cells are transduced with tumor specific CAR Process – blood drawn from patient T cells extracted using leukapheresis Transduction of T cells with retroviral vector encoding CARs CAR-T cells reintroduced into patient – two daily infusions “Warrior” T cells seek out & destroy enemy cancer cells Could be used in any cancer with a tumor antigen (ie: HER-2 in breast) Basically the T cells are programmed against patient’s own tumor cells Purwar R. Engineered T cells slideset 2016., Park JH. Conference Correspondent.ASH 2015 abstract 682.

CAR-T Therapy Advantages
Fast & high response rates – 91% CR pediatric ALL; 82% CR adult ALL No HLA typing needed (like with allogeneic HSCT) Side effects less harmful than chemo or allo HSCT Potential to target many antigens (protein, carbohydrate, lipids) Cut cost by at least 30% compared to allo HSCT Challenges Cytokine syndrome – treat with steroids Heavily pretreated patients may not have enough T cells Long-term sequelae & relapse rates currently unknown Adult trial – 82% (37/46 pts) CR, median time 21 days. 18 had prior allo, 6 month OS 71%, 24% had cytokine release syndrome. Did they relapse or die of other causes?? Professional killers – don’t need to have pre-existing immunity Learning more about preventing cytokine release Takes ~1 month to harvest & prime T cells – could store T cells sooner Purwar R. Engineered T cells slideset 2016., Park JH. Conference Correspondent.ASH 2015 abstract 682.

Immunovirus Therapeutic vaccine – different from prophylactic vaccines
Tumors & viruses have dynamic interactions Malignancy can suppress normal antiviral responses Many viruses preferentially infect cancer cells Viral infection can ravage a tumor while leaving adjacent healthy cells untouched Two mechanisms Modified virus can induce tumor cell lysis through replication within tumor cells Virus can activate T cell response against tumor antigens through dendritic cells Injected directly into tumors, but showing effect on cancer elsewhere in the body Like measles or polio – introduce Ag to immune system, not pt specific Goal is not to prevent, but to generate immune response Physicians in 1800s noted that cancer pts sometimes unexpectedly went into remission after experiencing a viral infection Sets off an alarm to the immune system Tumor releases antigens – introduced into dendritic cells (sentinels of the immune system) – generates potent antitumor immunity Ledford H. Nature 2015;526:622., Pietrangelo A. Heathline News

Immunovirus: Talimogene laherparepvec (Imlygic®)
First oncolytic viral therapy approved in the U.S. FDA (Oct 27, 2015) – local treatment of unresectable cutaneous, subQ, & nodal lesions in pts with melanoma recurrent after initial surgery Genetically modified herpes simplex virus – replicates in tumors & produces GM-CSF Causes cell lysis – releases tumor-derived antigens & GM-CSF Elicits further antitumor immune response OPTiM trial – phase III multicenter, open label, randomized 436 advanced melanoma patients; Imlygic® vs GM-CSF Extended survival by 4.4 months; time to response 4.1 months SE – fatigue, chills, fever, nausea, flu-like symptoms, injection site pain, cellulitis Being studied in combination with PD-1 inhibitors in melanoma & other solid tumors Altered to reduce ability to cause herpes GM-CSF attracts dendritic cells, which present tumor Ags to T cells programming them to destroy cancer cells throughout the body No effect on OS or visceral mets Endpt = durable response rate = % pts w/ CR or PR maintained >6mo; 16.3% DR vs 2.1% (p<0.0001). Some CRs SE – most resolved w/in 72 hours Antivirals may interfere with effectiveness Talmogene laherparepvec package insert

Immunovirus: PVS-RIPO
PVS-RIPO – genetically engineered poliovirus against GBM Genetic code of rhinovirus spliced into polivirus to remove it’s disease-causing ablility Safety – in primates & humans; no nerve cell damage, no ability to cause poliomyelitis, no ability for PVS-RIPO to change back to wild type poliovirus Infused directly into patient’s tumor Catheter placed into tumor, 2.5ml PVS-RIPO infused in the ICU over 6.5 hours, catheter removed, patient followed, no further treatment Kills tumor cells & recruits immune response vs. the tumor SE – fever, flu-like, diarrhea, headache, N/V, limb weakness, breathing difficulties, brain swelling, etc Future – phase II/III in adults, pediatric brain tumors, other tumor types (showing response in lung, breast, colon, liver, pancreas, kidney, etc) Survival for recurrent GBM?? Doubles every 2-4 weeks w/o treatment Receptor for poliovirus is present on most tumor cells Doesn’t kill normal cells because its ability to grow & kill depends on biochemical abnormalities only present in cancer cells Pt followed weeks 1,2,4,8 then Q8 wks. MRIs at weeks 4,8 then Q8 weeks Patients must have completed all standard care including resection & chemo/RT Gromeier M, et al

Immunovirus: What’s Next
Other promising virus therapies Breast cancer vaccine – targets HER-2 neu receptor CimaVax-EGF – lung cancer vaccine developed in Cuba Respiratory enteric orphan virus (Reolysin®) Ovarian cancer vaccine (>80% of patients have metastatic disease) Trials ongoing in lung, colon, melanoma, sarcoma, head & neck Room for improvement Need a way to deliver the vaccine systemically Requires a technique to prevent an immune attack to the virus prematurely Many viruses being studied Vesicular stomatitis virus that infects cattle but not humans Virus that hitch-hikes on certain blood cells camouflaged from immune system Difficult to reach all tumors with an injection May be a day when physicians will be able to peruse a menu of oncolytic viruses and select the best fit Cohn D. Innovations in Science

Chen DS, et al. Immunity. 2013;39:1-10.

Immunotherapy for the Future
BiTE Anitbodies Bridges a target antigen on surface of cancer cell to CD3+ on the cytotoxic T lymphocyte Engages T cell, bypassing MHC Ag-dependent activation of T cell T cells release proteolytic enzymes that lyse the tumor cell BiTE Ab then moves through bloodstream targeting other cells Activated T cells remain active Universal cancer biomarker??? DNA methylation mark around ZNF 154 found in 15 tumor types in 13 different organs Tumors often shed DNA into bloodstream Advantage – no prior knowledge of the cancer required Could be used to diagnose cancer earlier, monitor during treatment, or identify high risk patients And now for the wow factor of my presentation… NIH researchers Results from chemical modification of DNA called methylation (gene known as ZNF 154) – controls expression of genes like a dimmer on a light switch Less intrusive than other screening like colonoscopy or mammogram Imagine having a blood test to diagnose cancer Next – screening ovarian cancer pt blood samples BiTE antibodies News release NIH 2016 Feb

Currin R. CurrinBIOTECH Newsletter. 2011;1(10)

TMEM (tumor microenvironment of metastasis) Research has uncovered how breast cancer spreads TMEM - 3 specific cells coming together Tumors with high TMEM score are more likely to spread New drug target – could lead to treatments to stop cancer from spreading Magic wands Hand held probe connected to a laser that shines light onto human tissue Can distinguish cancer cells from normal cells Neurosurgeons testing on brain tumor patients during surgery Trials showing the probe detects cancer cells when they are there 95/100 times Cancer “doorway” 3 cells – endothelial cells that line blood vessel, perivascular macrophage found near blood vessel, & tumor cells that produces high level of mena (protein that encourages cells to spread) UC Davis research – detector reads fluorescence emission light generated by molecules in the illuminated tissue Cancer cells emit light with more intensity & specific amounts of time at certain wavelengths Use by surgeons to get all the cancer Pietrangelo A. Heathline News UC Davis Comprehensive Cancer Center

IDH2 Inhibitors IDH2 mutations have been identified in many solid tumors & hematologic malignancies 15% of AML patients – unlikely to respond to other treatments; majority in the study had relapsed or refractory disease IDH2 inhibitor (AG-221) – pill taken daily for AML ; ORR 56% (24 of 45 patients) with 15 CRs Allows AML cells to develop into healthy neutrophils SE – mostly disease-related rather than treatment-related Proteomics Assessing proteins in the blood for cancer screening Research ongoing in ovarian cancer, oral cancers, & lung cancer Intraoperative radiation Single shot of radiation during surgery Less SE & improved outcomes Very big deal in this patient population Similar to ATRA Testing saliva proteins for oral cancers & proteins in exhaled breath Imagine taking a breathalizer to detect early lung cancer! Mulcahy N. Medscape Crane K. US News

CRISPR technology Clustered regularly interspaced short palindromic repeats Gene editing technique used to inactivate genes & see what happens Can reveal which human genes are essential & which matter specifically to cancer cells Humans have 20,000 – 25,000 genes – between 1600 & 1800 of these are essential & less likely to carry mutations Essential genes in cell lines of 8 different cancers have been catalogued so far Goal – find genes that are expendable in healthy cells but crucial in tumors Not yet sure if we will find enough genes that differentiate cancer cells or if they will be targetable Project Achilles – initiative that will use CRISPR to search for specific weaknesses in over 500 cancer cell lines Almost 15 years since human genome project published. Didn’t have a way of manipulating genes in human cells until now CRISPR was invented billions of years ago by bacteria, as part of a defense system for hacking into the genes of invading viruses Like a film editor splicing a segment of a film strip with a new clip Imagine doing that with genes – snip out a piece & replace it with something that corrects a mutation that would cause disease Involves an enzyme called Cas9 that slices DNA, and a guide molecule that deploys Cas9 to the right target Essential genes are more strongly activated so less likely to mutate These genes represent the box of tricks that cancers use to thrive, but also weaknesses we can exploit to destroy cancer cells Moffat predicted some of the colon cancer cells he studied would be vulnerable to metformin while another group would succumb to linezolid – and he was right Could also help diminish diseases like CF, muscular dystrophy and HIV Controversy – fears of embryo editing leading to designer babies & changes to embryos that are permanent. International summit is being convened on ethical issues Yong E. The Atlantic Nov CBS News Nov

Patient Case #1: PD-1 Inhibitor
ED 33yo male with Hodgkins Lymphoma Apr 2011: standard chemo w/ ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) x6 cycles 2nd line chemo: GDP (gemcitabine, dexamethasone, cisplatin) 2012: autologous stem cell transplant → recurrence Salvage chemo: brentuximab vedotin (Adcetris®) Salvage chemo: GDP, MOPP (mechlorethamine, vincristine, procarbazine, prednisone), bendamustine Dec 2014: allogeneic stem cell transplant → recurrence Aug 2015: nivolumab → almost no evidence of disease Mention it’s an immune checkpoint inhibitor

Patient Case #2: CAR-T Therapy
JA 3yo male with Acute Lymphocytic Leukemia (ALL) 2013 – diagnosed at age 18 months 2 year battle chemotherapy → relapsed twice Allogeneic stem cell transplant → relapse Out of treatment options other than hospice CAR-T Therapy → no evidence of disease x 9 months Strongagainstcancer.org

Patient Case #3: Immunovirus
SL 20yo female with tennis ball sized GBM (glioblastoma multiforme) brain tumor 2011 – surgery; 98% removed Radiation & chemotherapy (temozolamide) Recurrence 2012 → 1st patient on Phase I Polio immunovirus trial at Duke University Treatment began in May → tumor is larger by June No evidence of tumor x3 years What do these 3 patients have in common?? Thanks to innovation and technology, they are alive today 60 Minutes: Killing Cancer Part 1 & 2, Mar 29, Available at

Assessment Question #1 The most prevalent immune cells targeted by monoclonal antibodies to kill cancer cells are: Plasma cells T cells Dendritic cells B cells

Assessment Question #2 Which of the following is a disadvantage of CAR-T therapy It is 30% more expensive than an allogeneic stem cell transplant HLA typing is needed before treatment can begin There are more side effects than with traditional chemotherapy We don’t know the long-term effects or curability of CAR-T therapy

Assessment Question #3 Which of the following is a disadvantage of using viruses to kill cancer cells? The virus may cause a viral infection in the patient Immunoviruses cannot be used if the patient has received prior chemotherapy The virus may not reach all tumor cells if the tumor has spread throughout the body Healthy cells surrounding the virus-infected tumor cells become damaged by the virus

Conclusions Cancer will soon be the #1 cause of death in the United States Cancer treatment is entering a new era – stimulating the patient’s own immune system to fight cancer Immune checkpoint inhibitors have demonstrated success in treating cancer patients with advanced disease CAR-T therapy is an exciting new way to target the immune system & may eventually replace allogeneic HSCT Immunoviruses are being used in innovative ways to treat cancer with some promising long-term results Technology will change how cancer is prevented, detected, and treated in amazing new ways Today’s patient cases illustrate how technology & innovations are providing new hope for cancer patients & their loved ones

References United States Cancer Statistics ( ). Available at: Help find a cure for childhood cancer. Available at: Sweeney N, et al. The value of innovation in oncology: recognizing emerging benefits over time. Boston Healthcare. May 2015 Goodman B et al. History of cancer timeline. Based on the book: The Emperor of All Maladies by Siddhartha Mukherjee. Available at: The History of Cancer. Available at: Mills D. Researchers applaud President Obama’s plan for “moonshot” against cancer. Available at: Jan 13, 2016. Dendreon Corporation. Cancer immunotherapy: fundamental concepts and emerging role Available at: BiTE Antibodies: designed to bridge T cells to cancer cells Available at:

References Pelly S. 60 Minutes: Killing Cancer Part 1 & 2. Mar 29, Available at Atkins MB et al. Immunotherapy in cancer: from principles to practice. Clinical Care Options slideset 2014. Bristol-Myers Squibb. Nivolumab package insert (revised 1/2016). Available at Merk. Pembrolizumab package insert (revised 12/2015). Available at Mulcahy N. PD-1 blockade arrives in hematologic cancer. American Society of Hematology 56th annual meeting, Dec Abstr Available at: Mills D. Drug used in Jimmy Carter’s cancer treatment among a new generation of immune therapies Dec. Available at

References Purwar R. Engineered T cells: next generation cancer immunotherapy. Slideset 2016. Park JH. CAR-modified T-Cells in adult patients with relapsed/refractory B cell ALL. Conference Correspondent ASH Abstr 682. Ledford H. Cancer-fighting viruses near market. Nature. 2015;526: Pietrangelo A. Immune systems now a major focus of cancer treatment research. Healthline News Available at: Gromeier M, et al. Targeting cancer with genetically engineered poliovirus (PVS-RIPO) Available at: Cohn D. Virus Therapy. Innovations in Science Available at News release. NIH researchers identify striking genomic signature shared by five types of cancer Feb. Available at:

References Pietrangelo A. Researchers find “doorway” that allows breast cancer to enter the bloodstream. Healthline News Available at: UC Davis Comprehensive Cancer Center. Magic wands and other innovations to find cancer Available at: Mulcahy N. No chemo: agent represents a new way of thinking about AML. Medscape Available at: Crane K. 7 Innovations in cancer therapy. US News Available at: Yong E. The new gene-editing technique that reveals cancer’s weaknesses. The Atlantic 2015 Nov. Available at: CBS News. Could revolutionary gene-editing technology end cancer? 2015 Nov. Available at:

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