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Can tumors be reverse-engineered to produce a local-acting vaccine

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Can tumors be reverse-engineered to produce a local-acting ‘vaccine’?

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Recent developments and novel strategies such as immunotherapies and targeted therapies have made significant advancements in cancer treatments. Long-term benefits have been demonstrated using these approaches, leading to multiple approvals from regulatory bodies.

Sadly, only some treated patients develop an objective tumor response with long-term survival benefits. On top of that, the systemic delivery of immunotherapies can be responsible for severe auto-immune toxicities.

More recently, intratumoral immunotherapy has emerged as a novel strategy that uses the tumor itself as a vaccine. By directly injecting immunostimulatory products into the tumor, priming of anti-tumor immunity can be achieved using just small amounts of the drug, leading to a systemic and durable clinical benefit.

Oncolytic virotherapy

An example of such an approach is the use of oncolytic viruses as therapeutic agents. These naturally or genetically engineered viruses can be injected into a tumor where they selectively replicate in and destroy tumor cells while leaving normal cells undamaged.

In 2015, the US FDA approved the first oncolytic virus immunotherapy for the treatment of cancer — T-VEC for melanoma. This treatment involves an engineered herpes virus that has been modified to be less likely to infect healthy cells as well as cause infected cancer cells to produce an immune-stimulating protein.

In other studies, oncolytic viruses have also been shown to induce anti-cancer immune responses that enhance the efficacy of checkpoint inhibitors, as demonstrated with BioLegend anti-PD-1 LEAF functional antibodies in melanoma models.1 This led to the belief that combinatory therapy of oncolytic vectors with checkpoint inhibitors could be a promising regimen for melanoma treatment.

Research in this field has also been boosted by advances in genetic engineering technology. As such, oncolytic viruses are showing promise as an effective anti-tumor strategy, used alone or in combination with other therapies.

Mitochondria-targeting immunotherapy

In addition to oncolytic viruses, further intratumoral immunotherapy approaches are also being explored. For example, a research group based at Nanjing University in China recently investigated the ability of a mitochondria-targeting immunogenic cell death (ICD) inducer to stimulate anti-tumor immunity.2 They focused on targeting the mitochondria because studies have shown that mitochondrial reactive oxygen species (mtROS) might play a role in anti-tumor immunity.

The team developed a mitochondria-targeting modification of fenofibric acid (Mito-FFa) and observed increasing mtROS generation with superior anti-tumor effects compared to fenofibric acid alone. In addition, when the team measured luminescence and absorbance using the VICTOR® Nivo multimode plate reader, they observed that more ATP, another ICD marker for immune activation, was released into extracellular spaces following Mito-FFa treatment.

And in a poorly immunogenic tumor model, a single intratumoral Mito-FFa injection turned “immune-cold tumors” into “immune-hot tumors”. The team believed that CD8+ T cells were integral to a strong anti-tumor response via cross-priming by dendritic cells. When they depleted CD8+ T cells with BioLegend Ultra-LEAF anti-CD8 antibodies, the Mito-FFa anti-tumor response was erased, as noted by flow cytometry, microscopy, and ELISA assays. This confirmed that the proinflammatory nature of the cross-primed CD8 T cells were essential for propagating the Mito-FFa response against primary tumors.

Future outlook

Novel intratumoral immunotherapy strategies hold tremendous potential for revolutionizing cancer treatment. These strategies offer a targeted and selective approach to destroying tumor cells while stimulating the immune system’s response. With ongoing research and clinical studies, we can hope fforor further breakthroughs in harnessing the power of intratumoral approaches and improving the prognosis for cancer patients.

References:
  1. Garofalo M, Bertinato L, Staniszewska M, Wieczorek M, Salmaso S, Schrom S, et al. Combination therapy of novel oncolytic adenovirus with Anti-PD1 resulted in enhanced anti-cancer effect in syngeneic immunocompetent melanoma mouse model. Pharmaceutics. 2021;13(4):547. doi:10.3390/pharmaceutics13040547
  2. Wang Y, Wang W, Gu R, Chen J, Chen Q, Lin T, et al. In situ vaccination with mitochondria‐targeting immunogenic death inducer elicits CD8+ T cell‐dependent anti-tumor immunity to boost tumor immunotherapy. Advanced Science. 2023; doi:10.1002/advs.202300286

 

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