Possible Reason for the Failure of Immunotherapy in Glioblastoma

One of the reasons for the failure of immunotherapy in the deadliest malignant brain tumor has been found.

Immunotherapies targeting specific tumor-infiltrating lymphocytes (TIL) (expressing the immune checkpoint molecule programmed cell death-1) show therapeutic promise in preclinical studies of glioblastoma. However, they fail in clinical trials.

The present study "Low tumour-infiltrating lymphocyte density in primary and recurrent glioblastoma", published in the journal Oncotarget, was set to find the answer for it.

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Glioblastomas are tumors that arise from astrocytes that make up the supportive tissue of the brain. Glioblastomas are usually highly malignant.

‘One of the reasons for the failure of anti-PD-1 immunotherapy in Glioblastoma (the deadliest malignant brain tumor) is due to a significantly higher number of CD8+ TILs and lower levels of TIL density and PD-1+ TILs levels. ’

Glioblastoma is one of the most common and deadly malignant brain and Central Nervous System Tumors. It accounts for ~56% of newly diagnosed brain tumors in Australia.

It is seen that the majority of both primary and recurrent tumors have a low density of TILs. While all the cases of tumors have CD3+ TILs. A significantly higher CD8+ TIL density was demonstrated by quantitative analysis of TILs at recurrence.

Moreover, between primary and recurrent groups, there was no difference observed in CD3+, CD4+ and PD-1+ TIL density. Treatment target like anti-PD-1 antibodies with immune checkpoint inhibition, blocks PD-1/PD-L1 interactions. This restores the effector T cell proliferation and function.

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Immunotherapy in Glioblastoma

In a specific type of cancer – melanoma, it was seen that response to anti-PD-1 immunotherapy is associated with a higher density of CD8+ TILs. However, earlier clinical trials that have been conducted using anti-PD-1 immunotherapy in glioblastoma, demonstrated limited success.

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Studies like the CheckMate 143 trial and similar ones demonstrated no significant overall survival benefit in recurrent glioblastoma with anti-PD-1 when compared to the anti-angiogenic drug bevacizumab.

However, another study (Cloughesy et a) states that anti-PD-1 therapy significantly increases the overall survival if given before and after recurrent tumor resection than only after recurrent surgery.

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"The level of T cell infiltration seen in this small cohort of matched primary and recurrent glioblastoma tissue was low. Though the number of CD8+ TILs was significantly higher in recurrent compared to primary tumours, overall TIL density at recurrence was still mild. PD-1+ TILs in particular were absent in the majority of our cases. Whether this is why many clinical trials using anti-PD-1 immunotherapy have not shown significant survival benefit in glioblastoma requires further investigation," say the Tooney Research Team.

Source-Medindia