HIV RESEARCH

HIV, like many viruses, often manages to escape complete destruction by the immune system through mutation of the peptide antigens presented by surface HLA proteins.  These ‘escape mutants’ are poorly recognised by the T cells that controlled the original infection, allowing the mutated virus time to replicate and spread.

In a collaborative effort involving Cardiff University Medical School, Adaptimmune Ltd. and the University of Pennsylvania School of Medicine, a highly unusual T cell clone specific for an immunodominant HIV-1 gag epitope SL9 (SLYNTVATL), detectable in 75% of HIV-infected patients, was isolated from a subject that had managed to control his HIV infection for many years without the need for anti-retroviral therapy.  Characterisation of the TCR from this clone showed not only an exceptionally high affinity for the wild-type HIV antigen (150 nM) but also a broad recognition profile covering the common HIV escape mutants, leaving the virus nowhere to hide. Subsequent engineering of the TCR by Adaptimmune enhanced the affinity of the TCR across all of the common HIV escape mutations to optimise the TCR for subsequent adoptive use¹.

HIV – CLINICAL DEVELOPMENT

An enhanced affinity TCR specific for the HIV-1 gag epitope SL9 (SLYNTVATL) has now completed preclinical development and received FDA approval to open enrolment in an open label, exploratory Phase I multiple arm study.  The trial opened in November 2009 and enrolment is ongoing to evaluate safety, tolerability and antiviral effects of escalating doses of a single administration of autologous T cells modified using lentiviral vectors expressing an increased affinity version of this gag-specific TCR.  The trial is being run in association with the University of Pennsylvania. 

CANCER RESEARCH & DEVELOPMENT:

The technology has also completed several levels of validation in cancer. Specifically, TCRs specific for certain cancer antigens (NY-ESO, Melan A, gp100, HTERT and MAGE A3) have been engineered at affinities of 10-400pM and tested in cellular studies.  These studies have shown that T cells expressing NY-ESO and Melan A antigen specific TCRs with affinities between 100nM and 5 µM show increased and specific activation in response to cancer cells expressing the respective antigen^2-3.  Other TCRs have lower thresholds of affinity enhancement for specific, enhanced activity against tumour cells (unpublished data).

Adaptimmune’s first cancer clinical candidate is based on a MAGE A3 TCR and is scheduled to begin clinical testing in Q1 2011.

REFERENCES

1. Riley et al. 2008 Nature Medicine, 14(12): 1390-5.
2. Zhao et al. 2007, The Journal of Immunology 179: 5845-5854.
3. Robbins et al. 2008, The Journal of Immunology 180: 6116-6131.