“Life will win over death, and light will win over darkness”– Volodymyr Zelenskyy, President of Ukraine
“I would not be here today if it wasn’t for you and your discovery” – said Tomas Dahl during the meeting in Stockholm. Tomas was one of the cancer patients who had the prestigious chance to share their story with the Nobel Laureates. He emerged cancer-free, after trying the cancer immunotherapy pioneered by 2018 Medicine Laureates James Allison and Tasuku Honjo.
The “Nobel approach” for cancer therapy by inhibiting negative immune regulation is for sure a breakthrough. Inhibitors of immune checkpoints, such as programmed death-1 receptor, programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now approved by FDA for the treatment of multiple cancers: skin melanoma, gastric cancers, squamous carcinoma of the lung and many others. Moreover, clinical trials are ongoing for cancers exiting in all possible localizations. But is that enough?
The Red Queen reminds us that “it takes all the running you can do, to keep in the same place”. To succeed in the evolutionary race, we are to keep fighting. Tumours are tricky because they can compromise checkpoint inhibitors in different ways. For instance, they can affect PD-L1 expression levels, recruit tumour-infiltrating lymphocytes, mutate and generate neoantigens, increase infiltration of myeloid-derived suppressor cells, etc. All these changes in the tumor microenvironment and genome, lead to the formation of ‘cold’ tumours that are resistant to therapy in some patients.
Therefore, the current question is how to switch non-infiltrated ‘cold’ tumours into more immunogenic, immune-infiltrated, ‘hot’ tumours? Or how to boost the antitumor immunity and help immune checkpoint inhibitors do their best to overcome cancer?
The history of cancer immunotherapy revealed some successful cases of pathogens and parasites potentiating an antitumor immune response- including Coley’s toxins, attenuated Listeria monocytogenes, Trypanosoma cruzi, Plasmodium sp. and oncolytic viruses. These approaches had limitations, but they created a good background for further studies. Toxoplasma. gondii (T. gondii) emerged as another superhero candidate in work published in the Journal for ImmunoTherapy of Cancer.
Toxoplasma gondii is an obligate intracellular parasitic protozoan that causes toxoplasmosis. In my knowledge, toxoplasmosis was connected with cats, however, T. gondii is capable of infecting virtually all warm-blooded animals, including humans. The point is that only humans who have compromised immune systems (like pregnant women, and growing fetuses) can develop serious clinical symptoms of toxoplasmosis. Most infected people have no symptoms at all. According to CDC, more than 40 million people in the U.S. carry the Toxoplasma parasite, knowingly or unknowingly.
Previous studies showed the ability of Toxoplasma strains to potentiate antitumor immunity and significantly extend mouse survival. The advantage in comparison with other pathogen-based immunotherapies is that the efficacy of T. gondii therapy was not affected by pre-existing chronic T. gondii infection or by pre-existing immunity.
Zhu and colleagues hypothesize that the ability of the T. gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint inhibitors.
In their study, the authors used the CRISPR-Cas9 system to construct attenuated T. gondii strain ΔGRA17 (deleted dense-granule proteins 17). Deletion of the GRA17 gene in the virulent strain partly attenuates the parasite’s virulence in mice; but still induces a strong adaptive immune response, associated with cytotoxic T cell activation, and increased expression of IL-12 and IFN-γ.
Preclinical mouse models of melanoma, Lewis lung carcinoma and colon adenocarcinoma were treated with the combination of ΔGRA17 tachyzoites (the rapidly growing stage of T. gondii) and anti-PD-L1 and compared with each treatment alone.
ΔGRA17-anti-PD-L1 mix led to immune infiltration, activation and expansion of DCs, CD4+ and CD8+ T cells, NK cells, and NKT cells at the site of injection. As a consequence, it suppressed tumor growth and significantly increased mice survival compared to monotherapy with either ΔGRA17 tachyzoites or anti-PD-L1.
Furthermore, intratumoral injection of ΔGRA17 affected not only local tumors but also distant ones and sensitized their microenvironment to systemic PD-L1 inhibitors. Thus, Toxoplasma strain allowed switching ‘cold’ tumours into ‘hot’ ones. Later, IFN-γ CD8+ cytotoxic T cells supported total tumor regression and completed the mission. Well done.
Data provided by Zhu and colleagues are promising. They established a working combination of attenuated T. gondii strain with checkpoint inhibitors. It has an advantage over for instance oncolytic viruses in lack of interference between immunity to T. gondii and the antitumor immunogenic effect. However, “if we want to get somewhere else, we must run at least twice as fast as that”. Precise molecular mechanisms of the “toxoplasma effect” are still poorly understood, and further studies are needed to improve the efficacy of anti-PD-L1 therapy.
So, keep going. We will definitely win the fight against cancer!
Zhu Y, Elsheikha HM, Wang J, et al. Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors. Journal for ImmunoTherapy of Cancer 2021; 9:e002970
Article author: Taras Baranovskyi. Taras is a medical doctor at Immunotherapy Clinic in Kyiv, Ukraine. His research is focused on developing new approaches for overcoming the antimicrobial resistance of Klebsiella pneumoniae. Also, Taras is a part of a team which spreads knowledge of immunology through the ‘Cup of Immunology’ project.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
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