Personalised Cancer Vaccine

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  • Overview
  • How PCVs Work
  • Potential of Combinations
Overview

Personalised cancer vaccine (PCV): an individualised approach to mobilising the antitumour immune response

Therapeutic vaccines have been a major area of research over the past few decades. Their ability to prime T cells and boost the immune response is particularly helpful in overcoming priming defects in tumours, which can be caused by1-3

  • Poor tumour immunogenicity
  • Tumour mechanisms that prevent dendritic cell maturation or create an immunosuppressive tumour microenvironment

Past studies of cancer vaccines have been largely unsuccessful due to their use of common tumour-associated self antigens. While these antigens can be easily detected and are shared across tumour types, as self antigens, they are subject to immune tolerance, resulting in weak or no T-cell response1,4

Advances in next generation sequencing (NGS) revealed the diversity of mutations present in tumours—including a subset of mutations that generate novel neoantigens that are unique to a patient’s tumour. Since these neoantigens are tumour specific and not expressed by normal cells, these nonself antigens are more likely to be recognised by the body as foreign, making them highly immunogenic and able to bypass central immune tolerance.1,5,6

Roche is investigating an mRNA-based personal cancer vaccine that can target selected neoantigens in each patient, creating an individualised approach that can be universally applied to a wide range of cancers.7,8

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How PCVs Work

PCVs can induce antitumour T-cell immunity in individual patients

The Roche PCV uses NGS and bioinformatics to design an individualised, mRNA-based therapeutic vaccine, which uses neoantigens specific to each patient’s cancer to induce high-affinity antitumour T-cell responses.5,8

  • PCV development
  • Immune priming and activation
PCV development

PCV development process5,9

Genomic sequencing

Neoantigen selection

PCV preparation

  • A patient’s tumour sample is sent for analysis
  • DNA is extracted from the patient’s tumour cells and is sequenced
  • By comparing the sequences of the patent's tumour mutations with germline DNA from normal cells, tumour mutations are identified
  • Using a proprietary neoantigen selection process, the immunologic potential of the tumour mutations are evaluated
  • The neoantigens most likely to elicit an immune response are selected
  • Neoantigens are encoded into mRNA and synthesised into an individualised vaccine that can be delivered intravenously

Genomic sequencing

  • A patient’s tumour sample is sent for analysis
  • DNA is extracted from the patient’s tumour cells and is sequenced
  • By comparing the sequences of the patent's tumour mutations with germline DNA from normal cells, tumour mutations are identified

 

Neoantigen selection

  • Using a proprietary neoantigen selection process, the immunologic potential of the tumour mutations are evaluated
  • The neoantigens most likely to elicit an immune response are selected

 

PCV preparation

  • Neoantigens are encoded into mRNA and synthesised into an individualised vaccine that can be delivered intravenously
Immune priming and activation

Effect of the PCV on the immune response3,5

  • PCV is taken up by dendritic cells with subsequent translation of the synthetic vaccine mRNA into neoantigens
  • The neoantigens are loaded onto major histocompatibility complex (MHC) molecules on the surface of the dendritic cells and are presented to T cells
  • T cell recognition of the MHC/neoantigen complex leads to the activation and proliferation of both CD8+ and CD4+ T cells
  • Activated T cells can then recognise tumour cells with high specificity, leading to tumour-cell killing
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Potential of Combinations

Combining PCV with PD-L1 inhibition may further enhance the antitumour response

PCV enhances T-cell priming and activation in the tumour microenvironment through an individualised approach focused on tumour-specific neoantigens. However, as with any immune response, adaptive immune resistance may occur. In studies with PCV, neoantigen-specific T cell subsets were shown to be PD-1–positive, and postvaccine lesions were shown to upregulate PD-L1, which could deactivate T cells.3,5,8

  • PD-L1 inhibition can overcome this adaptive immune resistance3
  • Use of PCV in combination with PD-L1 inhibition may restore several aspects of the cancer immunity cycle and enhances the anticancer immune response3,8

PD-L1=programmed death-ligand 1.

Roche is actively investigating PCV in combination with PD-L1 inhibition11

 

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References 
  1. Hacohen N, Fritsch EF, Carter TA, Lander ES, Wu CJ. Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol Res. 2013;1:11-15. PMID: 24777245
  2. Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity. 2013;39:38-48. PMID: 23890062
  3. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504. PMID: 27207108
  4. Capietto AH, Jhunjhunwala S, Delamarre L. Characterizing neoantigens for personalized cancer immunotherapy. Curr Opin Immunol. 2017;46:58-65. PMID: 28478383
  5. Vormehr M, Schrörs B, Boegel S, Löwer M, Türeci Ö, Sahin U. Mutanome engineered RNA immunotherapy: towards patient-centered tumor vaccination. J Immunol Res. 2015;2015:595363. PMID: 26844233
  6. Lu YC, Robbins PF. Cancer immunotherapy targeting neoantigens. Semin Immunol. 2016;28:22-27. PMID: 26653770
  7. BioNTech to enter into worldwide strategic collaboration with Genentech to develop individualized mRNA cancer therapies. BioNTech website. https://biontech.de/2016/09/21/biontech-enter-worldwide-strategic-collab.... Published September 21, 2016. Accessed April 16, 2018.
  8. Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547:222-226. PMID: 28678784
  9. Kranz LM, Diken M, Haas H, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534:396-401. PMID: 27281205
  10. Chen DS, Mellman I. Oncology meets immunology: the caner-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
  11. US National Institutes of Health. Clinicaltrials.gov/ct2/show/NCT03359239. Accessed April 16, 2018.

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