CVac

CVac, short for ‘Cancer Vaccine’, is a potential immunotherapeutic agent that developed in Australia. CVac works by attaching an adjuvant, mannan, to the tumor cell surface protein MUC1, a glycoprotein commonly expressed on a variety of cancers. CVac is often compared to the immunotherapeutic agent Provenge, which gained FDA approval in 2010.

CVac was developed by the biotechnology company Prima BioMed (Nasdaq: PBMD) through to Phase II clinical studies between 2001 and 2015. After inconclusive clinical data in ovarian cancer 2013 and 2014, Prima announced in February 2015 that it had ceased recruiting into CVAc clinical studies and was seeking commercial partners for the product.[1] Evidence from the CAN-003 Phase IIb study has suggested that the product may have utility in ovarian cancer patients in their second remission.[2]

Treatment method

CVac is an ex vivo dendritic cell priming technology involving MFP, or mannan fusion protein, where a fusion protein of MUC1 and Glutathione S-transferase is coupled to oxidized polymannose. The dendritic cells are the orchestrators of the immune system. ‘Priming’ dendritic cells involves exposing those cells to disease antigens in order to get the immune system to properly recognise the antigen and mount an appropriate response. With CVac this takes place outside the body of the patient (ex vivo), with dendritic cells obtained by leukapheresis. The antigen in this case is MUC1, known to be overexpressed on a variety of cancer cells[3] and in CVac MUC1 is conjugated to the carbohydrate mannan to facilitate uptake by the dendritic cells. CVAc can be administered subcutaneously, whereas Provenge is intravenous.[4]

Early development in Melbourne

CVac originated in the mid-1990s at the Austin Research Institute, a medical research facility then associated with Melbourne's Austin Hospital (and that merged with the Burnet Institute in 2006). The original version of the product was developed in the laboratory of the Austin Professor Ian McKenzie in 1993.[5] CVac therapy was originally intended to be in vivo but the Austin researchers started getting better results in ex vivo therapy.

Development by Prima BioMed

Prima BioMed was formed around 2001 to commercialise a number of Austin Research Institute projects including CVac. The company was taken public in July 2001 on the ASX in a reverse takeover of a defunct mineral explorer called Prima Resources.[6] CVac ultimately ended up as Prima BioMed's core project until Prima's acquisition of the French biotechnology company Immutep SA in 2014.

CAN-001 Phase Ib study, 2001-2003

CVac's original clinical study was a Phase Ib trial in ten patients which started in July 2001. In July 2003 PRR announced that two patients - one with kidney cancer and the other with ovarian cancer - had reached the two year mark without any further progression in their tumours. The results of the trial were published in February 2006 in the journal Clinical Cancer Research[7]

CAN-002 Phase IIa study, 2004-2007

In April 2004 a Phase IIa trial of CVac in 20 ovarian cancer patients obtained ethics approval. Recruitment for the trial, to be undertaken in Melbourne, commenced in around June 2004 and completed in 2006 with favourable data being reported in March 2007. Prima BioMed chose ovarian cancer because it was one of the two cancers that seemed to have the best response in the Phase I trial, and also because ovarian cancer has traditionally been associated with poorer outcomes than other cancers. In this study CVac showed stabilization of disease in four of the 21 patients, based on stabilization or reduction in the tumour marker CA-125. These results were published in the Journal for ImmunoTherapy of Cancer in June 2014.[8]

CAN-003 Phase IIb study, 2010-2015

CVac (a "MUC1 Dendritic Cell Vaccine") was taken into the Phase II 'CAN-003' study[9] in epithelial ovarian cancer in July 2010.[10] This study recruited 63 patients in either their first or second remission after previous therapies. The first seven patients were not randomised, with Prima using those patients to establish batch-to-batch manufacturing comparability for the product. The remaining 56 randomised 1:1 to either CVac or placebo.

In September 2013 Prima reported top-line interim data from this trial which showed no observed difference between treatment and control group in terms of Progression-free survival (PFS). For patients in the trial in their first remission the control (43 patients) median PFS favoured the control group. However, for patients in their second remission the advantage was to CVac, with PFS of 7.69 months versus 5.14 months for controls. This result was not statistically significant (p=0.09) but had a trend towards significance[11]

In May 2014, when Prima reported final PFS data from CAN-003, it was able to show median PFS for CVac patients in second remission of 12.91 months versus 4.94 months for the control group. This result had statistical significance (p=0.04)[12]

In November 2014 Prima reported that the median for Overall Survival (OS) in the second remission patients had not been reached after 36 months, which compared favourably with an estimated OS for standard-of-care patients of 25.5 months. This analysis had a p value of 0.07.[13] Prima reported final Overall Survival numbers for CAN-003 in May 2015. In this analysis the median survival number for CVac patients had still not been reached at 42 months and the p value remained 0.07.[14]

CAN-004 study, 2012-2015

Prima had originally intended that CAN-003 would be a lead-in to a Phase III study that was initially called CANVAS (Cancer Vaccine Study) and then CAN-004.This study was going to recruit 800 patients in remission across 150 centers in 22 countries in Europe, Australasia and the US with a primary endpoint of PFS. The study had started recruiting in February 2012 (ClinicalTrials.gov identifier NCT01521143). In November 2013, having considered the favorable trend data on second remission patients, announced that it was altering the protocol for CAN-004 in order to enrich it for second remission patients. The new protocol switched CAN-004 to a 210-patient Phase II randomised and controlled study for second remission patients, with a primary endpoint of Overall Survival. The amended protocols started gaining approval in January 2014 and patients started enrolling in April 2014. However, in February 2015 Prima announced that it was no longer recruiting into its CVac studies.

CAN-301 study in pancreatic cancer

In December 2014 Prima started recruitment for a new Phase I/II study in pancreatic cancer that would recruit up to 40 patients in a single-arm study as a proof of concept that CVac could work in cancers other than ovarian (ClinicalTrials.gov identifier NCT02310971). The patients would enter the study after resection of their tumor.[15] However this study was canceled in February 2015 along with CAN-004.

Approvals

CVac was approved for use by the Dubai Health City Authority in May 2011.[16]

In November 2013 Prima was able to attract Neopharm, an Israeli pharma company, as the licensing partner for Israel and the Palestinian Territories. This deal will see Neopharm buying the product from Prima and the two companies sharing profits.

Manufacturing

CVac was manufactured in Germany by Fraunhofer IZI (Das Fraunhofer-Institut für Zelltherapie und Immunologie), an institute of the Fraunhofer Society in Leipzig, Saxony[17] The Fraunhofer IZI was authorized to manufacture the treatment in Europe in late 2011 after meeting criteria laid down by the German Arzneimittelgesetz (Drug Law). Prima intended that its product would be manufactured at this one central location, with patient blood being flown to Leipzig and primed dendritic cells being shipped back to the relevant trial site.

Software platform

In late May 2015 Prima BioMed announced a collaboration with Database Integrations Inc (DBI), from Alpharetta, Georgia. DBI designed and built the iCAN software platform that managed electronic records and electronic signatures for CVac. Under the collaboration Prima and DBI will market the platform to other developers of cellular therapy worldwide.[18]

References

  1. ↑ "Prima BioMed Prioritising IMP321" (PDF). Prima BioMed market release. 27 February 2015. Retrieved 1 June 2015.
  2. ↑ "CVac Shows Clear Trend for Overall Survival Benefit in Second Remission Ovarian Cancer in Phase II Study" (PDF). Prima BioMed market release. 19 May 2015. Retrieved 1 June 2015.
  3. ↑ Rakha EA, Boyce RW, Abd El-Rehim D, Kurien T, Green AR, Paish EC, Robertson JF, Ellis IO (October 1, 2005). "Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer.". Mod Pathol. 18 (10): 1295–1304. doi:10.1038/modpathol.3800445. PMID 15976813.
  4. ↑ Schröder, L. (May 1, 2013). "Autologous immunotherapy for ovarian carcinoma – A new chance?" (PDF). Ärzteblatt Sachsen. Retrieved 1 June 2015.
  5. ↑ WO application 1995018145, Vasso Apostolopoulos, "Conjugates of human mucin and a carbohydrate polymer and their use in cancer treatment", published 1995-07-06, assigned to Austin Research Institute
  6. ↑ "Prima BioMed Ltd (formerly Prima Resources Ltd) - Reinstatement of securities to Official Quotation" (PDF). Australian Stock Exchange Participant Circular. 6 July 2001. Retrieved 1 June 2015.
  7. ↑ Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, Pietersz GA, Apostolopoulos V, Vaughan H, Karanikas V, Kyriakou P, McKenzie IF, Mitchell PL (February 1, 2006). "Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma.". Clin Cancer Res. 12 (3): 869–77. doi:10.1158/1078-0432.ccr-05-1574. PMID 16467101.
  8. ↑ Mitchell PL, Quinn MA, Grant PT, Allen DG, Jobling TW, White SC, Zhao A, Karanikas V, Vaughan H, Pietersz G, McKenzie IF, Gargosky SE, Loveland BE (June 18, 2014). "A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer.". J Immunother Cancer. 2 (16). doi:10.1186/2051-1426-2-16. PMID 24995129.
  9. ↑ Ovarian Cancer Vaccine for Patients in Remission
  10. ↑ "Prima BioMed has enrolled the first patient for the CVac Phase IIb trial" (PDF). Prima BioMed market release. 23 July 2015. Retrieved 1 June 2015.
  11. ↑ "Top-line analysis of CVac Phase II trial; Ovarian cancer clinical development update" (PDF). Prima BioMed market release. 18 September 2013. Retrieved 1 June 2015.
  12. ↑ "Prima BioMed's CVac Demonstrates Improvement in Progression-Free Survival in Second Remission Ovarian Cancer" (PDF). Prima BioMed market release. 15 May 2014. Retrieved 1 June 2015.
  13. ↑ "CVac demonstrates overall survival benefit in second remission ovarian cancer" (PDF). Prima BioMed market release. 6 November 2014. Retrieved 1 June 2015.
  14. ↑ "CVac Shows Clear Trend for Overall Survival Benefit in Second Remission Ovarian Cancer in Phase II Study" (PDF). Prima BioMed market release. 19 May 2015. Retrieved 1 June 2015.
  15. ↑ "Prima initiates pancreatic cancer trial with CVac" (PDF). Prima BioMed market release. 15 December 2014. Retrieved 1 June 2015.
  16. ↑ Ferris-Lay, Claire (2 June 2011). "New ovarian cancer treatment approved in Dubai". arabianbusiness.com. Retrieved 1 June 2015.
  17. ↑ "Fraunhofer IZI received manufacturing authorization for tumor vaccine CVac". Fraunhofer IZI press release. 28 October 2011. Archived from the original on 4 March 2016. Retrieved 1 June 2015.
  18. ↑ "Prima BioMed to Commercialise CVac's Database Management Platform". Prima BioMed. 25 May 2015. Retrieved 30 June 2015.

Further reading

External links

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