oncolytic virus

Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma

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Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is the first oncolytic viral immunotherapy to be approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma. Its direct intratumoral injection aim to trigger local and systemic immunologic responses leading to tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T-cells. Its approval has fueled the interest to study its possible sinergy with other immunotherapeutics in preclinical models as well as in clinical contextes. In fact, it has been shown that intratumoral administration of this immunostimulatory agent successfully synergizes with immune checkpoint inhibitors. The objectives of this review are to resume the current state of the art of T-VEC treatment when used in monotherapy or in combination with immune checkpoint inhibitors, describing the strong rationale of its development, the adverse events of interest and the clinical outcome in selected patient’s populations.

Abstract

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.

Conclusions

The landscape of options for advanced melanoma is rapidly improving and progressing, with drugs and combinations able to significantly expand patients’ window of expectations. However, adverse events occurring during treatment can limit the dose intensity and duration of those treatments, thus consequently affecting their effectiveness. Moreover, despite their tremendous impact on outcomes, most of the patients still relapse and die of their disease, leading to the need of expanding the therapeutic armamentarium with new drugs, sequences or combinations. Furthermore, with the advent of new technologies, therapeutic options are becoming more and more multidisciplinary, being surgery often avoided thanks to the adoption of new approaches requiring radiotherapy or interventional radiology expertise in order, for example, to reach visceral and deep internal lesions for intralesional injection of drugs.

T-VEC is the first genetically modified herpes simplex virus-1-based oncolytic immunotherapy approved by FDA and EMA for the treatment of unresectable, cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery [72,73]. This intratumoral injectable drug is designed to preferentially replicate in tumors, produce GMCSF, and stimulate antitumor immune responses both locally and systemically. As extensively discussed in this review, it has shown efficacy in monotherapy and in combination with immune checkpoints inhibitors.

Efficacy has been demonstrated mainly on injected lesion, but also an abscopal systemic effect was evident on metastasis in distant organs. Like most of the immunotherapies effectiveness is not immediately translatable is target lesion reduction and, instead, it is worth noting that progressive disease before observing a response is common both in patients treated with T-VEC alone or in combination with checkpoint inhibitors. This pattern of pseudo-progression has been widely described and reinforces the importance of continuing treatment beyond progression in the event of appearance of a new lesion or limited increase in existing ones [55,74].

In advanced melanoma, the combination of oncolytic viruses has been tested in clinical trials using T-VEC together with systemic administration of a checkpoint inhibitor: ipilimumab or pembrolizumab. A Phase 2 trial of T-VEC in combination with ipilimumab met its primary endpoint, resulting in a significantly higher ORR without additional safety signals than ipilimumab (39% vs. 18%, p = 0.002). Another Phase Ib trial tested the association of T-VEC and pembrolizumab with a confirmed ORR of 67% with a CR rate of 43%. In the coupled translational study, this association was able to increase CD8+ T cells, while PD-L1 and IFN-γ upregulation were observed in tumors from responders.

The positive effect of T-VEC, as a monotherapy or in combination with checkpoint inhibitors, which was observed in both injected and uninjected (including visceral) melanoma lesions, indicated that a systemic antitumor immune response was triggered. These results suggest that T-VEC may improve the efficacy of checkpoint inhibitor immunotherapies by changing the tumor microenvironment and support the rationale that combining immunotherapies with complementary mechanisms of action may yield augmented antitumor responses.

Interestingly, adverse events, both in monotherapy and in combination with immune checkpoints inhibitors are mild and easily reversible, leading to a new efficient and well tolerated treatment opportunity in those melanoma patients with injectable lesion and low tumor burden.

Trials are ongoing to confirm clinical results on larger number of patients and in comparison with the best standards of care, in order to confirm this approach is able to achieve high efficacy with low toxicity. Furthermore, new generation clinical trials incorporate regular sampling of both peripheral blood and tumor tissue, allowing basic and translational research, which will give insight on the mechanisms regulating tumor versus T-cells balance in the microenvironment and will characterize the immune response exploring its correlations with clinical outcomes.

This Incredible Virus Attacks Brain Cancer And Actually Boosts Our Immune System

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The first therapeutic virus to pass the blood-brain barrier.

A study attempting to show that viruses could be delivered to brain tumours has delivered that and more.

Not only did the virus in question reach its target, it also stimulated the patient’s own immune system – which then also attacked the tumour.

 

Preclinical experiments in mice, followed by window-of-opportunity trials in nine human patients, showed that the naturally occurring virus offers potential for a new type of cancer therapy that could be used alongside other treatments.

The virus they used is one that has previously shown potential for cancer treatment – what is known as an oncolytic virus.

It’s called mammalian orthoreovirus type 3, from the reovirus family, and it has previously been shown to kill tumour cells, but leave healthy cells alone.

Previous experiments have demonstrated this mechanism, but researchers from the University of Leeds are the first to successfully direct it at brain tumours.

This is because, until now, it was thought unlikely that the reovirus would be able to cross the blood-brain barrier, a membrane that protects the brain from pathogens.

“This is the first time it has been shown that a therapeutic virus is able to pass through the brain-blood barrier, and that opens up the possibility this type of immunotherapy could be used to treat more people with aggressive brain cancers,” co-lead author Adel Samson said.

Nine patients were selected to be injected with the virus via a single-dose intravenous drip. All either had brain tumours that had spread to other parts of the body, or fast-growing gliomas – a type of brain tumour that is difficult to treat and has a poor prognosis.

All were scheduled to have their brain tumours surgically removed in a matter of days following the reovirus experiment.

The researchers took samples from their tumours after they had been removed, and compared to the tumours of patients who had had brain surgery, but not the reovirus treatment beforehand.

The researchers found the virus in the tumour samples of the trial patients, clearly showing that the virus has been able to reach the cancer.

But they also found an elevated level of interferons, the proteins that activate our immune system. The team says that these interferons were attracting white blood cells to the site to fight the tumour.

“Our immune systems aren’t very good at ‘seeing’ cancers – partly because cancer cells look like our body’s own cells, and partly because cancers are good at telling immune cells to turn a blind eye. But the immune system is very good at seeing viruses,” said co-lead author Alan Melcher.

“In our study, we were able to show that reovirus could infect cancer cells in the brain. And, importantly, brain tumours infected with reovirus became much more visible to the immune system.”

These findings are already being applied in a clinical trial, where patients are being given the reovirus treatment in addition to chemotherapy and radiotherapy. One patient’s treatment is already underway – he is being given 16 doses of the reovirus to treat his glioblastoma.

The reason he is being given multiple doses is because of the way the virus activates the immune system. This clinical trial will determine how well cancer patients can tolerate the treatment, since the virus creates flu-like side effects, and whether it makes the standard treatments more effective.

“The presence of cancer in the brain dampens the body’s own immune system. The presence of the reovirus counteracts this and stimulates the defence system into action,” said one of the researchers, oncologist Susan Short, who is also leading the clinical trial.

“Our hope is that the additional effect of the virus on enhancing the body’s immune response to the tumour will increase the amount of tumour cells that are killed by the standard treatment, radiotherapy and chemotherapy.”