Aspirin’s synergistic role in cancer immunotherapy

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  • Aspirin use appears to improve survival post diagnosis in colorectal cancers  with certain genetic mutations 
  • Immune check point inhibitors against the PDCD1 (programmed cell death 1, PD-1) to CD274 (PDCD1 ligand, PD-1) axis have shown exciting clinical benefits in the treatment of refractory cancer.
  • Aspirin appears to have a synergistic effect with new immune check point blockade therapies.

The U.S. Food and Drug Administration (FDA) has approved the anti PDCD1 (PD-1) antibody pembrolizumab for the treatment of solid tumours that have high-level microsatellite instability (MSI) or mismatch repair deficiency. This has been seen as an exciting development in cancer therapy as it is the first anticancer agent license based on a tumour biomarker rather than the actual primary cancer site.

High- level MSI is often present in colorectal cancer which may be why immune check point blockade has helped to improve survival in this cancer type. Unfortunately not all MSI-high colorectal cancers respond to immunotherapy. There are many complexities to individual colorectal cancers which are influenced by lifestyle factors, the microbiome and host cells which are thought to result in unique genetic and epigenetic aberrations and a distinct microenvironment. Predictive factors for immune response are therefore required.

Aspirin may reduce colorectal cancer mortality by inhibition of PTGS2 and prostaglandin E2 (PGE2) synthesis. In addition aspirin appears to have immune enhancing effects on the adaptive and innate immune response

These effects seen with aspirin appear to be influenced by the genetic makeup of the cancer. Colorectal cancer with lower-level CD274 (PD-L1) expression appear to benefit from better post diagnosis aspirin use than those with higher-level CD274 expression.

Activation of the CD274-PDCD1 immune checkpoint pathway may result in resistance to aspirin therapy in colorectal cancer treatment. This may be overcome with the use of immune checkpoint blockade therapies. Immune check point therapy and aspirin may work in a synergistic manner to control the progression of colorectal cancer.

References

For further information see: Hamada T, Giannakis M and Ogino S Aspirin in the era of immunotherapy Oncotarget. 2017 Sept 26: 8(43):73370-73371.

References1. Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent strokeafter transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 2016; 18th May online.Recently published science of interestabout aspirin: aspirin mechanismIn an Opinion article in press at Nature Reviews Cancer, we review the weight of the evidence supporting aspirin’s chemopreventive potential and highlight advances in our understanding of aspirin’s mechanisms of action. We challenge the notionthat aspirin prevents cancer through a single, dominant pathway and propose an integrative multi-pathway model for itsmode of action. We highlight how these pathways can be leveraged to develop mechanistic biomarkers for personalised riskstratification. Such biomarkers may then be translated clinically in a precision medicine approach critical to the future of aspirinchemoprevention.

1.          Gaciong Z. The real dimension of analgesic activity ofaspirin. Thromb Res. 2003;110(5-6):361-4.

2.          Seymour RA, Hawkesford JE, Sykes J, Stillings M, HillCM. An investigation into the comparative efficacy of soluble aspirin and solidparacetamol in postoperative pain after third molar surgery. Br Dent J.2003;194(3):153- 7; discussion 49.

3.          LamplC, Voelker M, Steiner TJ. Aspirin is first-line treatment for migraine andepisodic tension-type headache regardless of headache intensity. Headache.2012;52(1):48-56.

4.          LecchiM, D’Alonzo L, Negro A, Martelletti P. Pharmacokinetics and safety of a newaspirin formulation for the acute treatment of primary headaches. Expert OpinDrug Metab Toxicol. 2014;10(10):1381-95.

5.          Eccles R, Loose I, Jawad M, Nyman L. Effects ofacetylsalicylic acid on sore throat pain and other pain symptoms associatedwith acute upper respiratory tract infection. Pain Med. 2003;4(2):118-24.

6.          Bachert C, Chuchalin AG, Eisebitt R, Netayzhenko VZ,Voelker M. Aspirin compared with acetaminophen in the treatment of fever andother symptoms of upper respiratory tract infection in adults: a multicenter,randomized, double-blind, double-dummy, placebo-controlled, parallel-group,single-dose, 6-hour dose-ranging
study. Clin Ther. 2005;27(7):993-1003.

7.          LeonardsJR. The influence of solubility on the rate of gastrointestinal absorption ofaspirin. Clin Pharmacol Ther. 1963;4:476-9.

8.          Davison C. Salicylate metabolism in man. Ann N Y AcadSci. 1971;179:249-68.

9.          Fonseca MD, Cunha FQ, Kashfi K, Cunha TM. NOSH-aspirin(NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reducesinflammatory pain. Pharmacol Res Perspect. 2015;3(3):e00133.

1.      Final Recommendation Statement: Aspirin Use toPrevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication.U.S. Preventive Services Task Force. April 2016.

2.      Bibbins-DomingoK; U.S. Preventive Services Task Force. Aspirin use for the primary preventionof cardiovascular disease and colorectal cancer: U.S. Preventive Services TaskForce recommendation statement. Ann Intern Med. 2016;164:836-45. doi:10.7326/M16-0577

3.      U.S.Preventive Services Task Force. Aspirin for the prevention of cardiovasculardisease: recommendation statement. AnnIntern Med 2009;150:396-404.

4.      DehmerSP, Maciosek MV, Flottemesch TJ, LaFrance AB, Whitlock EP. Aspirin for thePrimary Prevention of Cardiovascular Disease and Colorectal Cancer: A DecisionAnalysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun21;164(12):777-86.

5.      EA,Whitlock EP. Aspirin for the Primary Prevention of Cardiovascular Events: ASystematic Evidence Review for the U.S. Preventive Services Task Force.Evidence Synthesis No. 131. AHRQ Publication No.13-05195-EF-1. Rockville, MD:Agency for Healthcare Research and Quality; 2015. [PMID: 26491760]

6.      Chubak J, Kamineni A, Buist DSM, Anderson ML, WhitlockEP. Aspirin Use for the Prevention of Colorectal Cancer: An Updated SystematicEvidence Review for the U.S. Preventive Services Task Force. Evidence SynthesisNo. 133. AHRQ Publication No. 15-05228-EF-1. Rockville, MD: Agency forHealthcare Research and Quality; 2015. [PMID: 26491758]

7.      Whitlock EP, Williams SB, Burda BU, Feightner A, Beil T.Aspirin Use in Adults: Cancer, All-Cause Mortality and Harms. A SystematicEvidence Review for the U.S. Preventive Services Task Force. Evidence SynthesisNo. 132. AHRQ Publication No. 13-05193-EF-1.Rockville, MD: Agency forHealthcare Research and Quality; 2015.[PMID: 26491756]

8.      Guirguis-BlakeJM, Evans CV, Senger CA, O’Connor EA, Whitlock EP. Aspirin for the primary preventionof cardiovascular events: a systematic evidence review for the U.S. PreventiveServices Task Force. Ann Intern Med. 2016;164:804-13. doi:10.7326/M15-2113

9.      ChubakJ, Whitlock EP, Williams SB, Kamineni A, Burda BU, Buist DSM, et al. Aspirinfor the prevention of cancer incidence and mortality: systematic evidencereviews for the U.S. Preventive Services Task Force. Ann Intern Med.2016;164:814-25. doi:10.7326 /M15-2117

10.   WhitlockEP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks withaspirin use for primary prevention in adults: a systematic review for the U.S.Preventive Services Task Force. Ann Intern Med. 2016;164:826-35.doi:10.7326/M15-2112

Table 1 Studies examining PIK3CA mutation, aspirin use and colorectalcancer outcomes.

Study

%

PIK3CA Mutant

End­point

PIK3CA Mutant

PIK3CAWild-Type

No aspirin

Aspirin

HR (p value)

No aspirin

Aspirin

HR (p value)

Nurses’ Health Studyft Health Professionals Follow-up Study (Liao 2012)

16.7%

OS

95

66

0.54 (0.01)

466

337

0.94 (0.96)

CSS

–

–

0.18(<0.001)

–

–

0.96 (0.76)

VICTOR trial (Domingo 2013)

11.6%

OS

90

14

0.29 (0.19)

681

111

0.95 (0.26)

RFS

–

–

0.11 (0.027)

–

–

0.94 (0.79)

Moffitt Cancer Centre & Royal MelbourneHospital (Kothari 201S)

12.4%

OS

136

49

0.96 (0.86)

–

–

–

CSS

–

–

0.60 (0.14)

–

–

–

Eindhoven Cancer Registry (Reimen 2014)

15.8%

OS

73

27

0.73* (0.4)

348

147

0.55(<0.001)

Characteristic

No. of Patients

No. of Deaths

Univariate RR(95% CI)

P Value“

Adjusted RR (95% Ci)c

P Value“

HLA class Iantigen

 

 

 

 

 

 

Loss

 

 

 

 

 

 

No aspirin use

263

123

1 (Reference)

.74

1 (Reference)

.91

Aspirin use

57

26

1.08(0.70-1.64)

1.03(0.66-1.61)

Expression

 

 

 

 

 

 

No aspirin use

521

257

1 (Reference)

.003

1 (Reference)

<.001

Aspirin use

122

42

0.61(0.44-0.85)

0.53(0.38-0.74)

 

1.     Langley RE, Burdett S, Tierney JF, Cafferty F,Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as anadjuvant therapy? Br J Cancer. 2011; 105(8): 1107-13.

2.    Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A,Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidenceand mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754): 1741-50.

3.     Rothwell PM, Fowkes FG, Belch JF, Ogawa H,Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due tocancer: analysis of individual patient data from randomised trials. Lancet.2011; 377(9759): 31-41.

4.    RothwellPM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, et al.Short-term effects of daily aspirin on cancer incidence, mortality, andnon-vascular death: analysis of the time course of risks and benefits in 51randomised controlled trials. Lancet. 2012; 379(9826): 1602-12.

5.     Rothwell PM, Wilson M, Price JF, Belch JF, MeadeTW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study ofincident cancers during randomised controlled trials. Lancet. 2012.

6.     Coyle C, Cafferty FH and Langley RE. Aspirin andColorectal Cancer Prevention – Is it for everyone? Curr Colorectal Cancer Rep(2016) 12:27–34

7.    Reimers MS, Bastiaannet E, Langley RE, van Eijk R, vanVlierberghe RL, Lemmens VE, et al. Expression of HLA Class-I Antigen, AspirinUse, and Survival After a Diagnosis of Colon Cancer. JAMA Intern Med, 2014174(5) 732-739.

Current clinical trials of aspirin in Italy include ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular EventsPrevention Trial in Diabetes), a primary prevention trial coordinated by Dr. Nicolucci at the Mario Negri Institute in Milan,and ASAMET, a randomized, 2×2 biomarker prevention trial of low-dose aspirin and metformin in colon cancer patientscoordinated by Dr. De Censi at the E.O. Ospedali Galliera in Genova. Moreover, investigators in Rome, Chieti, Verona, Sienaand Bari, coordinated by Prof. Paola Patrignani, are collaborating in investigating the role of platelet activation in intestinaltumorigenesis. They will test the hypothesis that inhibition of platelet activation may explain the efficacy of low-dose aspirin as achemopreventive agent.Besides the references quoted in the text, the following may be of interest:Patrono C (2015) The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol 66:74-85.Scavone M, Femia EA, Caroppo V, Cattaneo M. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does notimpair the capacity of platelet to synthesize thromboxane A2.Eur Heart J. 2015 Oct 29. pii: ehv551. [Epub ahead of print]Chan AT, Ladabaum U. Where do we stand with aspirin for the prevention of colorectal cancer? The USPTF recommendations.Gastroenterology. 2015 Nov 18. pii: S0016-5085(15)01665-0. doi: 10.1053 / j.gastro.2015.11.018. [Epub ahead of print]ever forany consequences arising from any reliance placed on such information, views, opinions and other materials in lieu of professional medical advice.For further information please contactInternational Aspirin FoundationBower House34 Bower Mount RoadMaidstoneKent ME16 8AUTel: +44(0) 1622 320118Fax: +44(0) 1436 840194Email: aspirin@aspirin-foundation.comwww.aspirin-foundation.com

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Djp

Daniel José Piñeiro

ASSOCIATE
Name
Daniel José Piñeiro
Academic Affiliations:
Full Professor of Medicine, Universidad de Buenos Aires, Argentina Trustee, Board of Trustees, American College of Cardiology
Professional Setting:
My academic experience includes more than 40 years as a practicing medical doctor, teacher, and researcher. I have fulfilled these appointments in settings of vital social engagement and impact, most notably at the Hospital de Clínicas “José de San Martín” of the Universidad de Buenos Aires, a public hospital with high academic recognition. Additionally, I currently hold the position of Full Professor of Medicine at that same University.
Academic Activities:
  • International Meetings Participations: 180
  • Books-Editor: 1
  • Books Chapters: 39
  • Refereed Full Articles: 118 (listed in Pubmed: 29)
  • Refereed Abstracts: 221
  • Editorial Boards: 10
Profesional Associations:
  • 2005 President, Sociedad Argentina de Cardiología.
  • 2011-2013 President, Inter-American Society of Cardiology.
  • 2011-2013 Member (ex-officio), Board of Directors, World Heart Federation
  • 2017-2018 Member (at large), Board of Directors, World Heart Federation
  • 2018-2021 Trustee, Board of Trustees, American College of Cardiology
Chia

John Chia

Name
John Chia MBBS (Spore), MRCP (UK), FAMS (Spore)
Academic Affiliations:

Adjunct Associate Professor DUKE-NUS Graduate Medical School,
Consultant Oncologist Curie Oncology Singapore,
Visiting Consultant National Cancer Centre Singapore.

Discipline:

Medical Oncology

Scientific Interests:
  • Aspirin as adjuvant therapy in established cancers
  • Adoptive T cell therapy and Dendritic cell vaccines in the treatment of solid tumors
  • Clinical Trial Design and Management
Declaration of Conflicts of Interest:

In the past 3 years, I have received consultant fees from Tessa Therapeutics, Aslan Pharmaceuticals, Novartis, and AstraZeneca.

I received grant support for investigator-initiated research from:

  • National Medical Research Council Singapore
  • Bayer AG

I hold shares in:  Roche, BMS, AstraZeneca, Incyte, Teva Pharmaceuticals, Trillium Therapeutics, Compugen, Arrowhead pharmaceuticals, Emergex, QuantumDx and Halozyme Therapeutics

Badimon

Lina Badimon

Name
Lina Badimon BSc, PharmD, PhD, FESC, FAHA
Academic Affiliations:
Director of the Cardiovascular Science Program (ICCC) at the Hospital Santa Creu and San Pau, IIB-Sant Pau; CIBER CV. Director of the Cardiovascular Research Chair of the Autonomous University of Barcelona and Director of the UNESCO Chair in Biomedical Sciences Training and Research.
Discipline:
Pharmacology, Cardiovascular Disease
Scientific Interests:
Cardio-metabolic diseases, thrombosis, atherosclerosis and ischemic heart disease
Declaration of Conflicts of Interest:

I received consultant and speakers fees from Amgen, AstraZeneca, Bayer, Lilly and Sanofi.

    Ge

    Junbo Ge

    Name

    Jubo Ge

    Ge Junbo, male, was born in Wulian, Shandong province on Nov. 8, 1962. He is the member of Chinese Academy of Sciences, professor and doctoral supervisor. He received his doctor’s degree of Medicine from German Mayence University in 1993 and now works as the director for Shanghai Institute of Cardiovascular Disease and the Center for Stem Cells and Tissue Engineering, Fudan University. He is also the designate chairman of the Cardiovascular Disease Branch of Chinese Medical Association, council member of the Cardiovascular Angiography and Interventions Association, international consultant of the American Heart Association. In Dec. 2013, he was appointed as the vice president of Tongji University.

    Prof. Ge has been engaged in clinical and scientific research work of cardiovascular disease since 1987, and his research area covers the pathogenesis of coronary heart disease, early diagnosis and treatment plan optimization.

    Langley

    Ruth Langley

    Name
    Ruth Langley PhD, FRCP
    Academic Affiliations:
    Professor of Oncology and Clinical Trials, MRC Programme Leader and Chair of the Cancer Group, MRC Clinical Trials Unit at UCL, honorary consultant in medical oncology at the Brighton and Sussex University Hospital.
    Discipline:
    Medical oncologist; trialist
    Scientific Interests:
    • Aspirin
    • Gastro-oesophageal malignancy
    • Transdermal oestrogen in the treatment of prostate cancer
    • Trials methodology
    Declaration of Conflicts of Interest:
    Has received honorarium from Bayer
    Chan

    Andrew T Chan

    Name
    Andrew T. Chan MD, MPH
    Academic Affiliations:
    Chief, Clinical and Translational Epidemiology Unit, Vice Chair, Division of Gastroenterology, Massachusetts General Hospital, Boston, Co-leader, Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston.
    Discipline:
    Gastroenterology
    Scientific Interests:
    • The role of aspirin in the prevention of colorectal cancer and other cancers
    • The role of the gut microbiome in colorectal cancer and other chronic gastrointestinal diseases, including inflammatory bowel disease and diverticulitis
    • The role of diet and lifestyle in colorectal cancer and other chronic gastrointestinal cancers
    Declaration of Conflicts of Interest:

    AACR Honors Dr. Andrew T. Chan With 2019 AACR-Waun Ki Hong Award

    Click here to find the press release.

    I received consultant Bayer and Pfizer, Inc.

    I received grant support for investigator-initiated research from:

    • National Institutes of Health
    • National Cancer Institute
    • Crohn’s and Colitis Foundation
    • Bayer AG
    Gaziano

    Mike Gaziano

    Name
    J Michael Gaziano MD, MPH
    Academic Affiliations:

    Professor of Medicine, Harvard Medical School; Chief Division of Aging, Brigham and Women’s Hospital; Director of Preventive Cardiology and Director of Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System.
    Discipline: Cardiology and Epidemiology

    Scientific Interests:
    I am a chronic disease epidemiologist with a particular interest in the roles that individual lifestyle choices (diet, exercise, smoking), metabolic factors (obesity, high cholesterol, and hypertension), and biochemical and genetic markers play on the risk of cardiovascular disease and other chronic illnesses. Also, of interest is the impact that vascular disease has on other organ systems, including cognitive dysfunction and renal disease. I have an interest in the design of large-scale trials and observational studies nested in large health care systems using big data analytic techniques.
    Declaration of Conflicts of Interest:

    I received consultant and speaker fees Bayer.

    I received grant support as a principal investigator or co-investigator for research from the VA, DOD, NIH, Merck and Kowa.

    Rothwell

    Peter Rothwell

    PAST – CHAIR
    Name

    Peter M. Rothwell PhD, MD, FRCP, FMedSci

    Academic Affiliations:
    • Action Research Chair of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford;
    • Founding Director, Wolfson Centre for Prevention of Stroke and Dementia, University of Oxford;
    • Wellcome Trust Senior Investigator;
    • Emeritus NIHR Senior Investigator;
    • Theme Leader, Stroke and Vascular Dementia, NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford
    Discipline:
    Neurology and Stroke Medicine
    Scientific Interests:
    • Risks and benefits of aspirin;
    • Primary and secondary prevention of stroke;
    • Effects of blood pressure on the brain.
    Declaration of Conflicts of Interest:
    I received consultant and speakers fees from Bayer AG.

    Carlo Patrono

    CHAIR
    Name
    Carlo Patrono MD, FESC, FRCP
    Academic Affiliations:
    Adjunct Professor of Pharmacology at the Catholic University School of Medicine in Rome (Italy) and at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia (USA).
    Discipline:
    Clinical Pharmacology
    Scientific Interests:
    • Studying platelet activation and inhibition in diabetes mellitus
    • Studying platelet activation and inhibition in myeloproliferative neoplasms
    • Investigating the mechanism of action of low-dose aspirin in preventing colorectal cancer
    Declaration of Conflicts of Interest:

    I received consultant and speakers fees from Acticor Biotech,  Amgen,  Bayer, GlaxoSmithKline,  Tremeau,  Zambon.

    I received grant support for investigator-initiated research from:

    • AIFA (Italian Drug Agency)
    • Bayer AG
    • Cancer Research UK
    • European Commission, FP6 and FP7 Programmes

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