Advances in gene delivery and engineering of T and B cells: Implications for prevention, therapy and cure

SY12

Symposium

Track A - Basic science

Boulevard Auditorium/Channel 7

25 July 10:30 - 11:30

Moderators

Zhiwei CHEN
The University of Hong Kong, Hong Kong, SAR of China
Sarah PALMER
The Westmead Institute for Medical Research/University of Sydney, Australia

The approval of the first long-acting ARVs is a major recent advance in HIV prevention and therapy. In parallel, a variety of delivery technologies are being pursued, including genetic delivery strategies that may lead to long-term expression and greater access to HIV sanctuary sites to suppress viral replication, potentially eliminate infected cells or render target cells resistant to infection.

Presentations
Rapporteur Summary

10:30 5 min	Introduction Zhiwei CHEN The University of Hong Kong, Hong Kong, SAR of China Sarah PALMER The Westmead Institute for Medical Research/University of Sydney, Australia

10:35 10 min	mRNA delivery to generate CAR-T cells in vivo: Potential implications in HIV Hamideh PARHIZ University of Pennsylvania, United States

10:45 10 min	B cell engineering for the long-term production of anti-HIV molecules or immune enhancers Paula CANNON University of Southern California, United States

10:55 10 min	HIV broadly neutralizing antibody escapability drives therapeutic efficacy of vectored immunotherapy Alejandro BALAZS The Ragon Institute of MGH, MIT and Harvard, United States

11:05 25 min	Live Q&A Sarah PALMER The Westmead Institute for Medical Research/University of Sydney, Australia Paula CANNON University of Southern California, United States Hamideh PARHIZ University of Pennsylvania, United States Zhiwei CHEN The University of Hong Kong, Hong Kong, SAR of China Alejandro BALAZS The Ragon Institute of MGH, MIT and Harvard, United States

AUTHOR

Michael Roche

SUMMARY

In this session, engineering and delivery of gene technology was described to develop CAR-T cells; induce B cells to produce novel antibodies; and HIV escape from broadly neutralising antibody production through the use of adeno virus vectors.

HIGHLIGHTS

Hamideh Parhiz (University of Pennsylvania) described in vivo targeting of CRISPR lipid-nanoparticles. Targeting nanoparticles to the CD4 receptor on T cells with a CD4-specific antibody could redistribute them to spleen and lymph nodes. Further, CD4 targeted lipid nanoparticles containing CRISPR Cas9 mRNA and guide RNA targeting the CCR5 gene could knock out CCR5 expression in vitro. Paula Cannon (University of Southern California) discussed heavy chain antibodies (HCAbs) which are constructs that are spliced into the IgH gene and both the antigen recognition site and Fc domain can be altered. Researchers produced anti-HIV and anti-SIV versions that could be engineered into B cells and produced naturally. One anti-HIV version, J3 was further modified to enhance clearance of infected cells by NK cells. Using a humanised mouse model of HIV infection, Alejandro Balazs (Ragon Institute) described viral evolutionary pathways and fitness costs associated with escape from broadly neutralising antibodies. Antibodies with better traditional measures of breadth and potency such as PGDM1400 and N6 were less able to control viral replication compared to VRC07. Virus from animals treated with VRC07 had a more complex evolutionary path that involved significant fitness costs to achieve resistance. This could be quantified to generate an ‘escapability’ score.

CRITICAL ASSESSMENT

In vivo targeting offers a scalable and accessible approach compared to ex vivo modification for gene therapy. Removing CCR5 expression in vivo by CRISPR could give the benefits seen from successful cures of HIV by stem cell transplantation with few of the side effects. Gene editing of B cells to produce HCAbs is a promising approach to produce optimally designed antibodies with the right combination of antigen recognition and effector function. We may need to rethink measures used to quantify a ‘good’ neutralising antibody. Broadly neutralising antibodies with low ‘escapability’ may be the right choices in HIV prevention or cure.