Join A Breakthrough. Synchronisation. of Immunotherapy. Veterinarian. Information Guide. Using Serial C-Reactive Protein (CRP) Measurements in Dogs

Transcription

1 Join A Breakthrough Canine Clinical Trial Synchronisation of Immunotherapy Using Serial C-Reactive Protein (CRP) Measurements in Dogs Veterinarian Information Guide

2 Immune System Patterns - Emerging Evidence Evidence gathered over the past few years has made it clear that the immune system is not ignorant of the presence of cancer. Once triggered, the immune system works in a very controlled, sequential and time-dependent fashion to orchestrate a response. Finely tuned opposing forces of immunity and tolerance are operating at any given moment. This natural balance of on and off switches allow vigorous and selective responses while avoiding damaging responses to normal healthy tissue. Observations suggest that, in cancer, this on/ off cycle simply repeats constantly under complex feedback control. In fact, this complex regulation is likely to be the very problem that does not allow the immune system to gain sufficient momentum to destroy the cancer. It was further shown that the on-switch cells (T-Effectors) and the off-switch cells (T-Regulatory cells) divide synchronously over a very short time frame, a few days apart. Our technology demonstrated that this cyclic activity can be mapped by measuring the concentration of inflammatory markers in circulation. The theory is that if therapy can be timed correctly, the off switch cells can be destroyed using immunotherapeutic doses of a chemotherapy agent, killing T-Regulatory cells at the time of division and thus allowing the T-Effectors cells to overcome cancer over-regulation and progress to kill the cancer cells. Immune Cycle and the Timing of Treatment These immune cycles most likely represent cyclical immune activation and suppression against the cancer, with a cycle period of approximately 5 8 days. Biotempus researchers reported the discovery of a repeating immune cycle using serial blood measurements of C-reactive protein (CRP), a commonly used inflammatory marker that rises and falls over several days with the initiation and termination of the immune response. 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 therapy with a 12-hour window with the induction of a more successful clinical response. Rx 12 hrs - 7 Days 2 Synchronisation of Immunotherapy

3 Relevant Research Standard Chemotherapy is known to have an immunomodulatory impact in addition to its tumour targeted effect 1,2,3,7,8. The random initiation of therapy is likely to result in an approximate 5-10% complete response rate across the broad range of cancers 5. De-randomising the initiation of treatment with respect to the patient s own immune cycle may significantly improve this rate 3,4,7,8,9,10,11,12. There is evidence to support the notion that the timing of therapy with respect to a patient s immune cycle may significantly improve outcomes of treatment 1,2,3,4. The presence of cycling in a patient s immune system been observed across a range of cancer types and has been elucidated by frequent serial measurements of acute phase inflammatory markers such as CRP and other cytokines 3,6. CRP is known to rise and fall with initiation and termination of the immune response in the acute state and in the chronic state in the cancer patient. CRP is also known to be elevated and rise with disease progression and fall on successful treatment 6,7. A Pilot study conducted at ASAP Laboratory during demonstrated clear cycle mapping in 10 dogs, of those, 3 were treated and 2 had favourable responses. Successful Canine Cycle Mapping at ASAP Laboratory Hs - CRP mg/l 14 Patient: Serial CRP Immune Cycle trend analysis Rx Date Hs-CRP 15/12/ /12/ /12/ /12/ /12/ /12/ /12/ Hs - CRP mg/l Dog#1 Lymphoma (update 17/10/2014) 40 Rx Day Crp (- 7 Days) Rx date 8/1/ (- 5 Days) Rx Days Daisy the Dog Date Hs-CRP Day 5/01/ /01/ /01/ /01/ /01/ /01/ /01/ /01/ /01/ /01/ /01/ CRP mg/l Serial CRP profile (with trend analysis) (- 7 Days) 8 In Summary The cancer patient s immune system oscillates or cycles. It is proposed that this cycle creates narrow recurring therapeutic windows where the immune system can be manipulated to destroy the cancer. We wish to test and document this in our canine cancer patients Veterinarian Information Guide 3

4 The Trial. Fine tuning the therapeutic window of opportunity The trial offers an alternative to euthanasia for canine patients with advanced cancer. We are looking for 20 participating clinics only 3 randomized groups will be treated hours either side of the hypothesized optimal treatment time. A hour prior to optimal time B. On hypothesized optimal time C hours post optimal time Response will be analyzed and compared with the different groups. Process Steps Canine Project Summary Dog Immune Monitoring & Treatment Schematics Cytotoxic Chemotherapy Protocol Rx 12 hrs Preferred ChemoRx date Stylised immune Cycle periodicity Curve, determined from collected data and projected forward 2-3 weeks, with marked anticipated therapeutic windows. [CRP] Eg: 12/1/2014 (- 7 Days) - 7 Days Monitor / Analyse One - Two week data collection period (to ascertain hs-crp levels and presence and length of Cycle in days) Time (days) Project forward / Treat Pulse Rx accuratelty in time at calculated point Evaluate at 7-14 days REPEAT IF NESSASARY / UNTIL IT WORKS Discuss with owners (owner to sign consent form), provide information pack. Fill online patient recruitment and eligibility form Collect serial blood samples (daily or every 2nd day) over 1-2 weeks and measure CRP in-house (instrument provided) Enter CRP results into secure web portal daily or when tested Data is subject to trend analysis - Report sent back to doctor with predicted optimal treatment time Cyclophosphamide tablets are prescribed by veterinarian (provided) and administered by the veterinarian or owner Evaluate and record response (fill form online). Repeat in 2 weeks if necessary 4 Synchronisation of Immunotherapy

5 Step 1 Owner discussion and consent form signed SynchroniSat ion of Immunotherapy Using serial C-reaCtive Protein (CrP) MeasUreMents in Dogs owners InformatIon GuIde Step 2 Fill online patient recruitment and eligibility form Veterinarian Information Guide 5

6 Step 3 & 4 Measure CRP level in-house enter results into secure web portal Step 5 Data is subject to trend analysis -> Report sent back to doctor with optimal treatment time Synchronisation of Immunotherapy

7 Step 6 Cyclophosphamide is prescribed by veterinarian (provided) and administered by the veterinarian or owner In our trial Cyclophosphamide will be used PO as an immunotherapeutic agent by using its ability to kill rapidly dividing cells. This timed-approach will be targeting T-Regulatory lymphocytes at the exact time they are dividing. The hypothesized results is tipping the balance of circulating T-Effector / T-Regulatory cell populations in favor of the effector mechanism and this allows the patient s own immune system to eliminate the cancer. Step 7 Evaluate and record response (fill form on secure website) Follow Up Post Treatment Questionnaire Clinician Details Veterinarian's Name: Clinic / Hospital: Can you please detail what clinical changes were noticed, if any: Phone: Address and Postcode: Patient Details Patient Name: Age: Sex: Male / Female Weight: Type of Cancer: Was any tumour sizing or staging follow up performed e.g. imaging, biopsy, pathology? Yes / No If yes, provide details: Primary: Metastases: Please include details to support the progression and monitoring e.g. imaging, biopsy, pathology and a clinical history summary Details Was an immune cycle identified for the patient? Yes / No provide details: Was treatment give on the exact date? Yes / No Has the prognosis changed? Yes / No If yes, provide details: provide details: Has there been any complications? Yes / No If yes, provide details: Veterinarian Information Guide 7

8 Lab ID number: Date: 24 July 2014 CHEMOTHERAPY SYNCHRONISATION WITH CRP CYCLE MAPPING REPORT Patient: max Doe to: Dr John Smith Age: 8y.o practice: Chemo Vet Centre Breed: Boxer reference ID: Gender: m C ph: Type of Cancer: Mast Cell Stage: 2 Fax: Treatment Modality: Chemotherapy / Surgery admin@chemo.com.au Serial measurements of CRP were performed for this patient with the following results. Dates of Blood Collection and Respective CRP values 1. 30/06/ mg/l 5. 07/07/ mg/l 2. 02/07/ mg/l 6. 09/07/ mg/l 3. 04/07/ mg/l 7. 11/07/ mg/l 4. 05/07/ mg/l 8. 12/07/ mg/l This data was analysed and subject to trend analysis and forward projection model before applying Biotempus s proprietary algorithm to determine the dynamics of the patient s immune cycle. Based on this, a personalised treatment impact calendar was produced specifically for this patient. The results are presented in a user-friendly format showing the predicted optimal date for the initiation of therapy as well as the impact of initiating treatment on other dates. OPTIMAL DATE: WEDNESDAY 16 JULY 2014 The optimal date for initiating therapy identifies the next phase in the patient s immune cycle predicted to have the highest probability of achieving optimal response based on immunomodulation and coincides with the predicted emergence of T-Regulatory cells. 8 Synchronisation of Immunotherapy

9 What s next Join the breakthrough trial Help us cure cancer in dogs Please register your interest by completing our online form at Biotempus.com/vet. You can also register by visiting ASAP Lab website We are looking for 20 leading clinics around Australia to take part in this study. We will be making contact with selected clinics to schedule further training and installation of the CRP point of care instrument. A public media campaign will target potential pet owners and refer them to participating veterinarians who will be listed on our websites. Veterinarian Information Guide 9

10 About Us Biotempus Limited is developing and commercializing technologies for monitoring and leveraging immune system responses against disease. Biotempus s strength is our discovery and unique understanding of using the immune cycle to forecast greatly optimized treatment windows. Break-Through Invention for Treating Cancer Biotempus is unlocking the unmatched potential for timed immunotherapeutics to combat disease. We have developed a deep insight into how drug efficacy can be increased and toxicity reduced by synchronizing treatments in accordance with cycles within the patient s immune system. We believe our collaborations with scientific and clinical research partners will transform complete response rates in cancer, chronic infection and a range of autoimmune and degenerative diseases. We are actively engaging with clinicians and pharmaceutical scientists to revolutionize immunological treatments. Our proprietary approach applies equally to traditional agents such as chemotherapy as well as the old and newly emerging range of immune modulating agents and vaccines. Cancer immunotherapy is predicted to be the backbone of cancer treatments over the next decade. Today cancer immunotherapy has captured nearly 50% of the overall oncology drug market, generating about $41 billion in 2014 alone. No costs are associated with CRP measurements or Cyclophosphamide provision for this study. 10 Synchronisation of Immunotherapy

11 Notes: Inclusion Criteria: Dogs must have measureable disease with elevated CRP. Please note that not all dogs with cancer will have CRP elevation. In most cases CRP is elevated in the serum of late stage cancer patients, rises with disease progression and returns to normal levels with successful treatment. We estimate that in 10% of patients a discrete immune cycle cannot be mapped in the first attempt. No costs are associated with CRP measurements or Cyclophosphamide provision for this study. REFERENCES: 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 1990,71:90. 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) 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;7:102. Andre N, Carre M, Pasquier E (2014) Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol 2014; Jul;11(7): Additional Articles: 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: Veterinarian Information Guide 11

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