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Join a Breakthrough canine clinical trial of Immunotherapy Using serial C-reaCtive Protein (CrP) MeasUreMents in Dogs information Guide immune system Patterns - emerging evidence evidence gathered over the past few years agent, killing t-regulatory cells at the time of has made it clear that the immune system is division and thus allowing the t-effectors cells to not ignorant of the presence of cancer. once overcome cancer over-regulation and progress triggered, the immune system works in a very to kill the cancer cells.
controlled, sequential and time-dependent fashion to orchestrate a response. finely tuned immune cycle and the timing opposing forces of immunity and tolerance are operating at any given moment. this of treatment natural balance of "on" and "off" switches allow these immune cycles most likely represent vigorous and selective responses while avoiding cyclical immune activation and suppression damaging responses to normal healthy tissue. against the cancer, with a cycle period of approximately 5–8 days. Biotempus researchers observations suggest that, in cancer, this "on/ reported the discovery of a repeating "immune off" cycle simply repeats constantly under cycle" using serial blood measurements of complex feedback control. In fact, this complex C-reactive protein (Crp), a commonly used regulation is likely to be the very problem that inflammatory marker that rises and falls over does not allow the immune system to gain several days with the initiation and termination sufficient momentum to destroy the cancer. of the immune response. It was further shown that the "on-switch" researchers were further able to show that cells (t-effectors) and the "off-switch" cells the timing of cancer therapy with respect to (t-regulatory cells) divide synchronously over this cycle could be crucial in determining the a very short time frame, a few days apart. our success of treatment. By sequentially measuring technology demonstrated that this cyclic activity Crp before and around the time of treatment, can be mapped by measuring the concentration they were able to establish the position of the of inflammatory markers in circulation. the patient's underlying immune curve. they have theory is that if therapy can be timed correctly, been able to correlate the timing of therapy the "off switch" cells can be destroyed using with a 12-hour window with the induction of a immunotherapeutic doses of a chemotherapy more successful clinical response.
Synchronisation of immunotherapy relevant research • the presence of cycling in a patient's immune system been observed across a range of • Standard Chemotherapy is known to have cancer types and has been elucidated by an immunomodulatory impact in addition to frequent serial measurements of acute its tumour targeted effect 1,2,3,7,8. the random phase inflammatory markers such as Crp initiation of therapy is likely to result in an and other cytokines 3,6. Crp is known to rise approximate 5-10% complete response and fall with initiation and termination of the rate across the broad range of cancers5. immune response in the acute state and in De-randomising the initiation of treatment the chronic state in the cancer patient. Crp with respect to the patient's own immune cycle is also known to be elevated and rise with may significantly improve this rate3,4,7,8,9,10,11,12. disease progression and fall on successful • there is evidence to support the notion • a pilot study conducted at aSap Laboratory that the timing of therapy with respect to during 2014-15 demonstrated clear cycle a patient's immune cycle may significantly mapping in 10 dogs, of those, 3 were treated improve outcomes of treatment1,2,3,4. and 2 had favourable responses.
successful Canine Cycle Mapping at asaP laboratory 2014-15 Dog#1 Lymphoma (update 17/10/2014) Serial CRP Immune Cycle trend analysis Daisy the Dog
Serial C RP profile (with trend analysis) Daisy the Dog
Serial C RP profile (with trend analysis) Hs-CRP Day
In Summary
the cancer patient's immun Re system oscil ates 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 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 12-18 hours either side of the hypothesized optimal treatment a. 12-18 hour prior to optimal time B. on hypothesized optimal time C. 12-18 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 Stylised immune Cycle periodicityCurve, determined from collected Preferred ChemoRx date data and projected forward 2-3 weeks,with marked anticipated therapeuticwindows.
Monitor / Analyse Project forward / Treat Evaluate at 7-14 days One - Two week data collection period Pulse Rx accuratelty in time (to ascertain hs-CRP levels and at calculated point presence and length of Cycle in days) REPEAT IF NESSASARY / UNTIL IT WORKS 1. Discuss with owners (owner to sign consent 5. Data is subject to trend analysis - report form), provide information pack. sent back to doctor with predicted optimal 2. fill online patient recruitment and eligibility form 6. Cyclophosphamide tablets are prescribed by veterinarian (provided) and administered 3. Collect serial blood samples (daily or every by the veterinarian or owner 2nd day) over 1-2 weeks and measure Crp in-house (instrument provided) 7. evaluate and record response (fill form online). 4. enter Crp results into secure web repeat in 2 weeks if necessary portal daily or when tested Synchronisation of immunotherapy

owner discussion and consent form signed of Immunotherapy Using serial C-reaCtive Protein (CrP) MeasUreMents in Dogs InformatIon GuIde Fill online patient recruitment and eligibility form Veterinarian information Guide

Measure CrP level in-house – enter results into secure web portal Data is subject to trend analysis -> report sent back to doctor with optimal treatment time Synchronisation of immunotherapy

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.
evaluate and record response (fill form on secure website) Follow Up Post Treatment Questionnaire
Clinician Details
Veterinarian's Name: Clinic / Hospital: tail what clinical cha es were noticed, if an Address and Postcode: Patient Details
Sex: Male / Female Please include details to support the progression and monitoring e.g. imagi ng,
biopsy, pathology and a clinical history summary
Was an immune cycle identified for the patient ? Yes / No provide details: Was treatment give on the exact date? Yes / No provide details: Has there been any complications? Yes / No If yes, provide details: Veterinarian information Guide lab iD number: 14-038876 Date: 24 July 2014 CHEMOTHERAPY SYNCHRONISATION WITH CRP CYCLE MAPPING REPORT
reference ID: 567890 mast Cel Stage: 2 treatment modality: Chemotherapy / Surgery Serial measurements of Crp were performed for this patient with the following results.
Dates of Blood Collection and respective CrP values
1. 30/06/2014 - 4 mg/L
5. 07/07/2014 - 4 mg/L
2. 02/07/2014 - 3 mg/L
6. 09/07/2014 - 3 mg/L
3. 04/07/2014 - 2 mg/L
7. 11/07/2014 - 2 mg/L
4. 05/07/2014 - 3 mg/L
8. 12/07/2014 - 3 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 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.
Synchronisation of immunotherapy 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 wil target potential pet owners and refer them to participating veterinarians who will be listed on our websites.
Veterinarian information Guide 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 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.
Synchronisation of immunotherapy 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.
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 2. 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):2648-62.
3. 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;4:958–975.
5. 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;4:137-49.
6. al in Kh, Bojesen Se, nordestgaard BG. Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin oncol. 2009 may 1;27(13):2217-24. 7. 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 8. andre n, Carre m, pasquier e (2014) metronomics: towards personalized chemotherapy? nat rev Clin oncol 2014; Jul;11(7):413-31. additional articles: 9. ashdown mL, Coventry BJ. a matter of time. australasian Science. may 2010:18–20.
10. Coventry BJ, et al. Immuno-chemotherapy using repeated vaccine treatment can produce successful clinical responses in advanced metastatic melanoma. J Cancer ther. 2010;1:205–213.
11. Dutcher Jp, Wiernik ph. Deconstructing and reinventing the IL-2 paradigm: Can alternate Dosing Schedules enhance tumor effect? Kidney Cancer Journal June 2013;11:1. 22-26.
12. ashdown mL, Coventry BJ. Window of opportunity. australasian Science. June 2014:16–19.
Veterinarian information Guide

Source: http://www.biotempus.com.au/wp-content/uploads/2015/09/WEB-ASAP-Synchronization-of-Immunotherapy-Canine-Cancer.pdf