Talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer

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Published: 15 Apr 2019
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Dr Hatem Soliman - Moffitt Cancer Centre, Tampa, USA

Dr Hatem Soliman speaks to ecancer at the 2019 American Association for Cancer Research (AACR) meeting about results from a study looking at the use of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer.

He explains that the TVEC, an oncolytic virus modified to limit it's replication to in cancer cells, was incorporated with a taxane and anthracycline.

Dr Soliman reports that the combination was safe and feasible with no unexpected toxicities and that 55% of patients saw a complete eradication of the tumour from the breast.

 

My presentation yesterday was the results of one of our exciting phase I trials currently enrolling patients at the Moffitt Cancer Centre. It’s titled a phase I trial of TVEC, which is short for talimogene laherparepvec, it’s a mouthful, for the treatment of non-metastatic triple negative breast cancer. As many physicians and patients are aware, triple negative breast cancer, while it represents a minority of the cases, approximately 10-15% of the cases we diagnose globally, is a particularly difficult to treat type of breast cancer with a relatively poor prognosis and higher risk of relapse. So there’s a dire need for novel therapies in this subset of breast cancer.

The typical rates of complete response with standard preoperative chemotherapy in this setting is around 30% and the goal of the study is to try to incorporate a novel treatment in order to boost that complete response rate and do a better job of completely eradicating the tumour. So the intent of the study is to incorporate an oncolytic virus which has been FDA approved in the United States for the treatment of melanoma. The virus, which is known as TVEC is directly injected into a tumour; it’s a genetically engineered version of what’s known as the herpes simplex virus, the virus that causes cold sores, but this virus has been engineered in order to limit its replication within cancer cells and prevent it from replicating normally within regular tissue. So that provides a margin of safety for using the virus against cancer cells whilst sparing the rest of the body.

Our trial was able to incorporate this TVEC agent alongside the preoperative chemotherapy which consisted of a taxane and an anthracycline and the results were quite striking for the treatment. Our phase I study was able to demonstrate that the combination was safe and feasible with no new unexpected toxicities and only expected side effects from the use of TVEC which generally include mild flu-like symptoms that are easily manageable. The notable safety signal that we noticed as well was that in patients that are getting the injection there was no significant interruption of the administration of chemotherapy so we were able to maintain the planned administration of the neoadjuvant chemotherapy without a lot of unplanned interruptions.

The efficacy, while it’s still preliminary it’s not the primary endpoint of the study, was quite promising. In 55% of the patients we noted a complete eradication of the tumour from the breast and from the draining lymph nodes and four additional patients out of the nine that were treated had almost complete eradication of their tumour. So while it didn’t meet the strict criteria for pathologic complete response, all nine patients demonstrated a significant amount of response to the incorporation of TVEC alongside their neoadjuvant chemotherapy. So it was quite a striking finding indicating that this combination is definitely worthy of continued study.

What is the virus’s molecular mechanism of action?

The TVEC virus’s mechanism of action as to how it kills cancer cells is that they have basically engineered out some of the virulence factors, as we call them, that allow the natural wildtype herpes simplex virus to replicate within the nerve tissue and mucosal tissues in a human being. So that in essence the virus specifically is only able to replicate in a permissive environment within transformed cancer cells. The basis of that mechanism is that we all have a natural defence mechanism in our normal cells called interferon and interferon is able to abort the replication of many viruses. In essence the body tries to kill off cancer cells by mounting an immune response, however this immune response fails over time which is why people eventually get diagnosed with cancer and the cancer is able to spread, it’s a failure of the host’s immune response. So by injecting these tumour cells with TVEC the virus is able to replicate quite well within tumour cells leading to the rupture of these cancer cells and a release of the tumour associated antigens that in the context of a viral infection leads to a set of danger signals being promulgated within the tumour. This awakens the immune system to take up those tumour associated antigens, present them in the proper way so you have a productive adaptive immune response to eradicate the tumour. That’s, in essence, the molecular action mechanism of action of TVEC within tumour cells – it’s meant to try to not only lice [?] the tumour cells directly through viral replication but awaken the immune system so that it can better target those cancer cells and eradicate them from the body from within. It’s almost like a Trojan Horse, if you will, that will get into those cells and alert the body to the fact that there is a target here that needs to be eradicated. That’s really the key signal that TVEC can provide to the body’s immune system.

What are the benefits of an oncolytic virus?

The benefit of an oncolytic virus in the treatment of cancer is that oncolytic viruses thrive in cancer cells that have properties that they require in order to keep them immortal. So cancer cells need to be able to stop themselves from dying. They also have to be able to thwart some of the immune system’s natural mechanisms of defence so that they’re not eradicated by the host immune system. All those things work in the virus’s favour so that it can exploit those properties of cancer cells that they use to propagate and stay alive to their advantage and replicate more efficiently and kill them off.

One issue is that cancer cells frequently will develop resistance to existing immune treatments, either through downregulating the target that the immune system may see or by using other proteins or signals to dull down the immune response and to be able to escape. Oncolytic viruses are able to somewhat prevent that from happening because the tumour cells do not have as good of a coping mechanism to overcome the ability of those viruses which have perfected their function over millions of years of evolution to target these cells and replicate. Oncolytic viruses, in my mind, are an ideal agent, especially against triple negative breast cancer, to overcome some of these resistance mechanisms and to create hot tumours where they were cold before and get a more effective anti-tumour immune response.

The timeline for when we think oncolytic viruses would be regularly incorporated into the treatment of cancer, I feel, is at hand and there is a tipping point of momentum that’s building with the use of these agents. I think it’s evidenced by the fact that multiple pharma companies are beginning to pay attention to oncolytic viruses and incorporating them into their early pipeline. As evidenced by some of the presentations here at AACR, a number of large pharma companies are already beginning to take on oncolytic viruses as part of their repertoire of tools for immuno-oncology.

One of the key developments that has allowed a lot of the pioneering research that has been built up from the work of many scientists, such as Dr Bell from the University of Ottawa and others, that the molecular tools required to genetically engineer the viruses have come a long way over the past several years so that it allows for ever more complex manipulations of the viral genomes to incorporate not only the safety properties that I described earlier to restrict the replication of the virus within the tumour cells but also allows the viruses to be what we call armed with additional immuno-oncology agents that the virus can encode for so that you can have an oncolytic virus basically bring its own anti-PD1, for example, or anti-CTLA-4 so that it negates the need for you to give a second drug alongside the oncolytic virus to make it work better. These kinds of armed viruses are potentially very exciting developments in the field that could promote a widespread use of these agents in the treatment of multiple tumour types.

Another important thing with oncolytic viruses is they’re not necessarily tumour type specific. They might likely be able to replicate within a wide variety of tumours in order to provide these benefits for a majority of patients with cancer.

Is there anything you’d like to add?

One thing to keep in mind is that as oncolytic viruses are developed many of these oncolytic viruses do need to be directly injected into the tumour because they can get rapidly eliminated by the body when they’re injected in the bloodstream. There are techniques and viruses which are being developed in order to potentially allow for the intravenous administration of these oncolytic viruses to get around that requirement which would further simplify the use of these viruses and allow them to be used more widely for the treatment of patients with metastatic disease which is a challenge because we can’t necessarily inject every metastatic site directly from a safety and practicality perspective. So that is something that needs to be worked on in order to further broaden the use of the agents.