Date: 4th September 2020
Chimeric antigen receptor (CAR) T cell therapies are part of the next generation of ‘living’ drugs designed to treat cancer. The foundation of CAR-T immunotherapy is to modify T cells to recognise cancer cells in order to more effectively target and destroy them. However, the identification of antigens that are truly confined to tumours is a major challenge and poses safety concerns. Now scientists have successfully combined oncolytic virus and CAR T cell therapy to target and eradicate solid tumours in mice.
There are currently only three CAR T cells therapeutic agents approved by the Food and Drug Administration (FDA), and all are for patients with B cell malignancies. Furthermore, all of them target CD19, an antigen highly restricted to the surface of B-cells, making it an ideal target against haematological malignancies.
However, finding appropriate antigen targets for treating solid tumours has been limiting as most are not restricted to the tumours, and they are usually expressed heterogeneously within the tumour itself. This has inhibited the potential for effective and durable anti-tumour responses in these types of cancers.
Now scientists from the City of Hope National Medical Center, US, led by Saul Priceman and Stephen Forman have addressed this roadblock by combining two powerful immunotherapies. By genetically engineered an oncolytic virus to target tumour cells they have forced these cells to express CD19 protein on their cell surface. The scientists were then able to use CD19-directed CAR T cells to recognise and attack these solid tumours.
To start the team used an oncolytic chimeric orthopoxvirus (OV), designed to infect a large spectrum of tumours, carrying a truncated version of the human CD19 under the control of a synthetic early promoter. The team showed that the OV was able to deliver CD19 to a variety of solid tumours in vitro, with nearly 100% of the tumour cells being positive for CD19 is most cases. Importantly, they found a time frame where expression of CD19 was high but the OV had not yet had time to kill the cancerous cells, providing a potential window of opportunity for targeting by the CD19-specific CAR T cells.
With this window in mind, the team then tested whether CD19-CAR T cells would be targeted to the tumour cells expressing CD19. Indeed, in vitro OV delivery of CD19 to the solid tumour cells was able to redirect activity and cytotoxicity of the CD19-CAR T cells, killing around 60-70% of the cells in the tumour.
To evaluate the combo therapy in a more clinically-relevant setting the team assessed the anti-tumour effects in human tumour xenograft models. Mice bearing subcutaneous tumours were injected with the dual therapy and showed significant slowing of tumour growth compared with the controls animals.
However, whilst the initial data was promising the team wanted to optimise the system for mice hoping to increase the efficacy. Therefore, they switched to a fully murine system, replacing the human version of CD19 with the mouse sequence, and using a mouse solid tumour model. Here they found a complete regression was achieved in ~60% of mice treated with the dual therapy. Reduction in tumour burden and improved overall survival was also observed in a metastatic mouse model on treatment with the dual therapy suggesting thisl therapy was a potent combination.
One unexpected, but beneficial, side effect was that the CD19-CAR T cell–mediated tumour killing promoted viral particle release and infection of tumour cells. It is likely that this was due to dying cells releasing the OV particles which could then infect surrounding cells, this led to a more homogenous OV infection throughout the tumour.
Further benefits to the system were seen as OV infection induced local immunity, this was realised by an infiltration of endogenous T cells. Furthermore, the virus reversed the tumour’s harsh microenvironment, making it more receptive to receiving CAR T cell therapy.
Interestingly, mice treated with the combo therapy developed tumour-specific immune memory. When the team rechallenged mice who been previously cured by the dual therapy, they failed to grow new tumours. This is an exciting feature and may help to reduce or even stop tumour recurrences.
Conclusions and future applications
The team have demonstrated the capability of OV to deliver a CAR-targetable tumour antigen to solid tumours, using both local tumour and regional metastasis models. The team therefore, propose that this antigen delivery method could be clinically translated for tumour types that lack amenable tumour antigens providing a new method for delivering safe and effective targeting by CD19-CAR T cells.
The translation into the clinical is already underway and the team are now designing a clinical trial to test this combination in patients. It is likely the first step will be to test the safety of the OV therapy alone, then if found to be safe and effective, the OV and CAR T cell therapy could then be tested in combination.
The team also plan to further modify the OV’s to express checkpoint pathway inhibitors, cytokines, and chemokines to augment CAR T cell trafficking to tumours and enhance their anti-tumour activities.
Whilst, this work adds to the increasing plethora of ‘living’ cancer drugs such as CRISPR-edited T cells, non-pathogenic bacteria, or macrophages used as delivery systems to name but a few, this is a real step forward in finding a solution to treating solid tumours. It is hoped that clinical trials for the dual therapy will be starting in 2022.
For more information please see the press release from the City of Hope Medical Center
Park, A. K., Y. Fong, S.-I. Kim, J. Yang, J. P. Murad, J. Lu, B. Jeang, W.-C. Chang, N. G. Chen, S. H. Thomas, S. J. Forman and S. J. Priceman (2020). “Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors.” Science Translational Medicine 12(559): eaaz1863.
https://doi.org/10.1126/scitranslmed.aaz1863
