Synchronization of Chemotherapy with the Immune Cycle Using Serial C- Reactive Protein (hs-crp) Measurements in Dogs

Transcription

1 Synchronization of Chemotherapy with the Immune Cycle Using Serial C- Reactive Protein (hs-crp) Measurements in Dogs

2 What we will cover tonight Immune System Interaction with Cancer The Immune Cycle Discovery Human Data ASAP Canine Clinical Trial

3 Immune System Interaction with Cancer Evidence gathered over the past few decades has made it clear that the immune system is not ignorant of the presence of cancer. Once triggered, the immune system switches on and off in a very controlled, sequential and time-dependent fashion. Klatzmann 2009 Observations suggest that, in cancer, this on/off cycle simply repeats constantly under complex feedback control. In fact, it is suggested that when this complex regulation stops working properly, it creates a problem that disturbs the balance where the off forces predominates.

4 COMPLEX INTERACTION

5 ON and OFF SWITCHES

6 ON SWITCH Immune response against the tumour = ON SWITCH is managed by T-Effector Cells Riordan Clinic 2013

7 OFF SWITCH The OFF-switch cells, called T-regulatory cells, tone the immune response down and acts like the brakes of a car. T-regs are responsible for Tumour Immunity or the induction of active immune tolerance or protection of the tumour from the immune system T effector cells

8 Multiple Treg Suppressive Modules & their Adaptability A two module model of Treg function. Foxp3 acts to control the core module of Treg suppressive function by regulating expression of a number of key molecules such as CTLA-4 and CD25. This allows Tregs to suppress T-effector activation and proliferation by suppressing APC function via CTLA-4 and possibly depriving IL-2 from other T cells. An additional Thχ-like module of suppressive function may also be induced that causes Tregs to express Thχ-like transcription factors allowing the Tregs to take on some of the properties of Th1, Th2, Th17, or follicular T cells, travel to the same sites and deliver in situ suppression. James B.Wing 2012

9 Selectively killing T-regs is allowing the unregulated immune system to destroy the tumour. North 1989 Klatzmann 2009

10 Effect of Timing Klatzmann 2009

11 Immune Cycle Discovery In the early 2000's Early trials at the University of Western Australia, on mice who had been deliberately infected with the murine version of AIDS ("MAIDS"). Such infected mice typically died within weeks of contracting the disease. However, we were able to demonstrate an immune cycle within these mice - and when we then treated these mice at a precise window within their individual immune cycles - these mice did not die (!) "Timed Ablation of Regulatory CD4+ T cells Can Prevent Murine AIDS Progression" was published in 2004, in "The Journal of Immunology"

12 Immune Cycle Discovery In 2005, researchers also documented the immune cycle using serial blood measurements of C-reactive protein (CRP), a commonly used inflammatory marker. Both T regs and T effector cells divide synchronously over a very short time frame a few days apart. These immune cycles most likely represent cyclical immune activation and suppression against the cancer, with a cycle period of approximately 6 8 days.

13 Researchers were further able to show that the timing of cancer therapy with respect to this cycle could be crucial in determining the success of treatment. By sequentially measuring CRP before and around the time of treatment, they were able to establish the position of the patient s underlying immune curve. They have been able to correlate the timing of chemotherapy with a hour window with the induction of a more successful clinical response.

14

15

16

17

18 Mayo Clinic Exploratory Chemotherapy Phase II Trial, MC057f Summary: N=12, Patients monitored for 2 weeks, then treated Evaluated for response to Rx WRT position on CRP cycle ASCO 2009, J Clin Oncol 27, 2009 (suppl; abstr e20013)

19

20 Future Prospects with Cancer Vaccines No appreciable toxicity was observed. Complete Responses (CR)occurred in 16.7% (9) and partial responses (PR) in 14.8% (8 Coventry et al. Journal for Immunotherapy of Cancer - April 2014

21 In Summary The cancer patient s immune system oscillates or cycles. It is proposed that this cycle creates narrow recurring therapeutic windows. We wish to test and document this in our canine cancer patients.

22 ASAP Clinical Trial DEPI WSIAEC reg Immune Synchronization of Chemotherapy with the Canine Immune Cycle Using Serial High Sensitive C-Reactive Protein (hs-crp) Measurements. Work done so far ASAP developed and validated high sensitivity CRP testing in Canines Successfully mapping Canine cycles with ImmuneAid both in Switzerland Zurich University and here in Melbourne

23 ASAP Clinical Trial DEPI WSIAEC reg Patient Inclusion Criteria only suitable for patients that have not been considering treatment or referral and where euthanasia is the most likely possibility. Informed and signed consents Measurable CRP levels Limited to patients with metastatic / advanced disease. Patients must be clinically stable who are relatively well. Exclusions: Patients who suffer from and are currently being treated for any chronic inflammatory or immune mediated disease conditions. i.e. rheumatoid arthritis, diabetes, severe atopy, infections, trauma etc.

24 Initially we will only offer its services to patients with the following cancers: Oral Squamous Cell Carcinoma Mammary Carcinoma Urinary Transitional Cell Carcinoma Chondrosarcoma Hemangiosarcoma Lymphoma and Lymphosarcoma Mast Cell Tumors Osteosarcoma Melanoma Thyroid Carcinoma

25 Lab testing and logistics Blood samples will be collected daily or EOD at participating veterinary clinics and analysed at ASAP laboratory at no cost to the clinic. Clinics will be contacted with optimal treatment day and receive a report

26 Sample Vet Report

27 Treatment Treatment will consist of using a single dose of the chemotherapeutic agent at the recommended date and time day that best suits the patient's individual immune cycle Cyclophosphamide at a dose of 25-50mg/sqm Per Os This may be repeated in 1-2 week intervals up to 3 cycle mapping times in total.

28 Monitoring Participating veterinarians will report outcomes on a standardized form recording: > Accurate cycle identified > Response to Tx (clinical, tumour size etc) > Complications CRP levels can also be monitored 1,2,3 and 8 weeks following the first chemotherapy

29 Process Steps Summary Collect Serial Bloods (daily or every 2 nd day) over 1-2 weeks Measure hs-crp in the lab send results to ImmunAid Data is subject to trend analysis and forward projection model Report sent back to vet with optimal treatment time Single dose chemotherapy treatment is provided by the vet Evaluate response Repeat above if necessary

30

31 How to Take Part Contact ASAP via > Information pack will be sent to you with Clinic information pack (incl registration form, trial protocol and selected publications) Owner consent form (customisable to clinic) Patient information pack (incl owners trial summary and chemotherapy safety information)

32 References 1. North, R. J, and M. Awwad. Elimination of cycling CD4_ suppressor T cells with an anti-mitotic drug releases non-cycling CD8_ T cells to cause regression of an advanced lymphoma. Immunology 1990,71: Darrasse-Jèze G, Bergot A-S, Durgeau A, Billiard F, Salomon BL, Cohen JL, Bellier B, Podsypanina K,Klatzmann D: Tumor emergence is sensed by self-specific CD44 hi memory Tregs that create a dominant tolerogenic environment for tumors in mice. J Clin Invest 2009, 119(9): F. Quevedo, M. L. Ashdown, V. J. Suman, A. Robinson, L. A. Kottschade, J. S. Kaur, E. T. Creagan, R. R.McWilliams, S. N. Markovic. Possible therapeutic reversal of immune suppression in patients with metastatic melanoma by timed delivery of temozolomide chemotherapy: A pilot study. J Clin Oncol 27, 2009 (suppl;abstr e20013) 4. Leontovich AA, Dronca RS, Suman VJ, et al. Fluctuation of systemic immunity in melanoma and implications for timing of therapy. Front Biosci (Elite Ed). 2012;4: Coventry BJ, Ashdown ML. Complete clinical responses to cancer therapy caused by multiple divergent approaches: a repeating theme lost in translation. Cancer Manag Res. 2012;4: Allin KH, Bojesen SE, Nordestgaard BG. Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol May 1;27(13): Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke SL, Robinson AP. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool? J Transl Med.2009;7: Andre N, Carre M, Pasquier E (2014) Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol 2014; Jul;11(7): Additional Articles: 9. Ashdown ML, Coventry BJ. A Matter of Time. Australasian Science. May 2010: Coventry BJ, et al. Immuno-chemotherapy using repeated vaccine treatment can produce successful clinical responses in advanced metastatic melanoma. J Cancer Ther. 2010;1: Dutcher JP, Wiernik PH. Deconstructing and Reinventing the IL-2 Paradigm: Can Alternate Dosing Schedules Enhance Tumor Effect? Kidney Cancer Journal June 2013;11: Ashdown ML, Coventry BJ. Window of Opportunity. Australasian Science. June 2014:16 19.

33 Questions