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Immuno-Oncology

Molecular TemplatesImmuno-Oncology

ANTIGEN SEEDING TECHNOLOGY (AST)

ETBs self-route to the cytosol where they can intersect with the cell’s antigen presentation pathway. Molecular Templates is exploting the localization of ETBs to the cytosol to create a novel immuno-oncology approach we call Antigen Seeding Technology (AST). With AST, ETBs can be used to deliver foreign class I antigens to the cytosol of tumor cells where the antigens can be processed and displayed in complex with MHC class I molecules on the cell surface. Tumor cells expressing the foreign peptide/MHC class I complex on their cell surface can be targeted for destruction by native high-avidity cytotoxic T-cells resident in the patient.

 

AST and Cytomegalovirus

Infection rates with cytomegalovirus (CMV) range from 40% to >90% across human populations. CMV infection can be latent with persistent viral reactivation. Persistent reactivation can lead to T-cell progressive memory inflation causing CMV-specific CD8+ T-cells to eventually dominant the memory component of CD8+ T-cells in infected individuals.1

 

CMV-specific CD8+ T cells retain cytotoxic activity and generally do not express high levels of PD-1 or other exhaustion markers. Because of the need to control persistent reactivation, CMV-specific T-cells may be protected from canonical mechanisms of exhaustion. Reactivation of CMV, for example, rarely occurs in CLL patients despite these patents having a generally exhausted T-cell profile. CMV-specific T-cells in CLL patients have decreased levels of PD-1, CD160, and CD244 relative to non-CMV specific T-Cells two and demonstrate equivalent killing activity against peptide-loaded targets compared to samples from healthy matched controls. 2

 

The CMV pp65 class I antigen is the main antigen used for antigen seeding. This antigen was chosen because of the high prevalence of specific effector T-Cells in the general population, with up to 20% of T-cells in elderly patients specifically reactive to pp65.3,4

 

Molecular Templates believes AST has the potential to be a novel approach to immuno-oncology that is both distinct and complementary to the two predominant approaches to date: checkpoint inhibition and chimeric antigen receptors.

RECRUITING A HIGH AVIDITY NATIVE RESPONSE TO THE TUMOR

  1. Sylwester et al. Broadly Targeted Human Cytomegalovirus-Specific CD4+ and CD8+ T Cells Dominate the Memory Compartments of Exposed Subjects. JEM, V202; 5: 673-685.
  2. Te Raa et al. CMV-specific CD8+ T-cell function is not impaired in chronic lymphocytic leukemia. Blood. 2014; 123(5):717-724).
  3. Vescovini et al. Massive Load of Functional Effector CD4+ and CD8+ T Cells against Cytomegalovirus in Very Old Subjects. J Immunol 2007; 179:4283-4291.
  4. Khan et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 2002. 169: 1984-1992.