Immune checkpoint inhibitors may work in brain cancers

November 21, 2014

Lugano/Geneva, Switzerland, 21 November 2014 - New evidence that immune checkpoint inhibitors may work in glioblastoma and brain metastases was presented today by Dr Anna Sophie Berghoff at the ESMO Symposium on Immuno-Oncology 2014 in Geneva, Switzerland.

The novel research shows that brain metastases have dense concentrations of tumour infiltrating lymphocytes, providing an immunoactive environment. Moreover, both primary and secondary brain cancers often exhibit high expression of the immunosuppressive factor programmed cell death ligand 1 (PDL1), which can be inhibited by new treatments, thus activating the immune system.

Berghoff, resident at the Department of Medicine I, Comprehensive Cancer Centre-CNS Tumours Unit, Medical University of Vienna, Austria, said: "Patients with glioblastoma and brain metastases have very few treatment options and usually die within a short period of time."

Immune checkpoint inhibitors are a new group of cancer treatments that work by boosting the patient's immune response to the tumour. The immune system operates differently in the brain in comparison to other organs. "Our study was designed to find out whether the immune system is activated and working in brain tumours, which would provide the foundation for immune checkpoint inhibitors to work," Berghoff explained.

The study included 117 patients with glioblastoma and 116 patients with brain metastases. Using immunohistochemistry the researchers looked for the presence of T-cells --also called tumour infiltrating lymphocytes-- in the tumours and whether they were accentuated in different areas of the tumour. T-cells are the main effector cells of the immune response and can be boosted by immune checkpoint inhibitors. They also looked for PDL1 --an immunosuppressive protein that influences responses to immune checkpoint inhibitors.

The researchers found that patients with glioblastoma had fewer T-cells, and therefore less activation of the immune system, than patients with brain metastases who had high concentrations of T-cells. They also found that PDL1 was common in both glioblastoma and brain metastases, with glioblastoma showing particularly high PDL1 positivity.

Berghoff said: "We saw that these brain tumour types have a different interaction with the immune system. The glioblastoma actively suppresses the immune system and there is little immune response. In contrast the brain metastases do a little less suppression of the immune system and there are a lot more tumour infiltrating lymphocytes."

Berghoff said the findings demonstrate that the immune system interacts with glioblastoma and brain metastases, which is evidence that immune checkpoint inhibitors may work: "We have arguments for conducting clinical studies with immune checkpoint inhibitors in patients with glioblastoma and brain metastases. In both tumour types we commonly see high expression of PDL1, an immunosuppressive factor which can be inhibited with new treatments. By inhibiting the suppression you can activate the immune system which in theory would work in brain cancers."

She continued: "We know that immune checkpoint inhibitors are more effective in immunoactive microenvironments. In brain metastases we see dense infiltration with T-cells which provides a good background for immune checkpoint inhibitors."

Small preliminary studies have shown efficacy of immune checkpoint inhibitors in melanoma brain metastases. However, melanoma is only the third most common brain metastases, the most common being non-small-cell lung cancer. Immune checkpoint inhibitors are active in extracranial metastasised lung cancer but it is unknown whether this holds true for patients with brain metastases. Data on immune checkpoint inhibitors in glioblastoma exists only in mice.

Berghoff said: "Our study shows that T-cells and PDL1 expression are present in glioblastoma and brain metastases. This means that the targets for novel drugs that activate the immune system against cancer cells are present and brain tumours may be effectively treatable with such drugs."

She concluded: "Our data strongly support the launch of clinical trials with immune checkpoint inhibitors, especially the ones targeting the PD1/PDL1 axis, in patients with glioblastoma and brain metastases. Indeed, some early studies are being designed and started at the moment. In addition, profiling of other immune checkpoint molecules and modes of immune escape in brain tumours need to be identified to prepare for the development of next generation immunomodulators."

Commenting on the implications of the findings for patients with glioblastoma and brain metastases, Professor Martin J. van den Bent, of the Neuro-Oncology Unit, Erasmus Medical Centre, Rotterdam, the Netherlands, said: "The investigators found different immune reactions to the malignant process in the brain that were related to the type of cancer. It is quite interesting that the immune system does play a role in brain metastases as well. The findings indicate that therapeutic interventions for brain cancers that use the immune system should be explored."

Van den Bent noted that brain metastases are not a homogenous group but vary depending on the primary tumour. He said: "I would guess that the type of immune reaction to brain metastases will differ between the various tumour types. We know that the mechanism with which metastases arise can be completely different between the various diseases."

"The debate on the penetration through the intact blood brain barrier and how significant that is for treatment effectiveness is still on the table," continued van den Bent. "But the general understanding is that any therapy that works for a specific type of cancer will also work if it has metastasised to the brain provided the access is good."
-end-
Notes

1O - Role of PDL1 expression and tumour infiltrating lymphocytes (TILs) in glioblastoma (GBM) and brain metastases (BM)"

Session

1O - Friday, November 21 2014 - Session 6 - 17:25 CET.

Disclaimer

Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.

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The European Society for Medical Oncology (ESMO) is the leading European professional organization committed to advancing the specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care.

ESMO's mission is to advance cancer care and cure through fostering and disseminating good science that leads to better medicine and determines best practice.

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Abstract: 1O

1O - ROLE OF PDL1 EXPRESSION AND TUMOR INFILTRATING LYMPHOCYTES (TILS) IN GLIOBLASTOMA (GBM) AND BRAIN METASTASES (BM)

A.S. Berghoff1, A.W. Wöhrer2, G. Widhalm3, F. Oberndorfer4, K. Dieckmann5, M. Filipits1, C. Marosi1, C. Höller6, W. Wick7, M. Preusser1 1Department of Medicine I, Medical University of Vienna, Vienna, AUSTRIA, 2Institute of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 3Department of Neurosurgery, Medical University of Vienna, Vienna, AUSTRIA, 4Clinical Institute of Pathology, Medical University of Vienna, Vienna AUSTRIA, 5Department of Radiotherapy, Medical University of Vienna, Vienna, AUSTRIA, 6Department of Dermatology, Medical University of Vienna, Vienna, AUSTRIA, 7Neurology Clinic and National Center for Tumor Disease, University of Heidelberg, Heidelberg, GERMANY

Background: Differences in the adaptive immune response to various kinds of brain tumors have been poorly characterized.

Methods: We immunostained 287 neurosurgical specimens: 170 BM (lung cancer: 77 (45.3%); breast cancer: 17 (10.0%); melanoma 44 (25.9%); renal cell carcinoma 10 (5.9%) others 22 (7.7%)) and 117 GBM for CD3 (n=287), CD8 (n=287), PD1 (n=287) and PDL1 (n=234) and used previously published semiquantitative evaluation criteria.

Results: TIL infiltration of variable density (sparse to dense) was found in 161/170 (94.7%) BM and 78/117 (66.6%) GBM. TILs were predominantly present in the tumor stroma and perivascular areas in BM and in perivascular area in GBM. Dense infiltration with CD3+ TILs (p<0.001), CD8+ TILs (p<0.001) and PD1+ TILs (p<0.001) was observed more frequently in BM than GBM. Among BM, we found significant differences in the composition of immune infiltrates with renal cell carcinoma BM showing the highest density of CD3+ and PD1+ TILs. Membranous PDL1 expression on tumor cells was evident in 25/117 (21.4%) BM and 44/117 (37.6%) GBM. Expression of PDL1 in over 5% of tumor cells was more frequently observed in GBM than in BM (p=0.006). Dense infiltration of CD3+ TILs (9 vs. 12 months; p=0.015) correlated with favorable survival prognosis in BM patients, while no prognostic impact of TIL infiltration was evident in GBM. Expression of PDL1 in over 5% of tumor cells was not associated with survival prognosis in BM (11 vs. 11 months; p=0.395) or GBM (15 vs. 14 months; p=0.859).

Conclusion: We found high TIL densities and prognostic impact of CD3+ immune infiltrates in BM. GBM was characterized by sparse TIL infiltrates, higher expression of PDL1 and lack of prognostic impact of immune infiltrates. Our results indicate clinically relevant differences in the immune response to brain tumor types and may be of interest for studies with immunomodulatory agents.

Disclosure: All authors have declared no conflicts of interest.

Keywords: Tumor infiltrating T cells, PD-L1, brain metastases, glioblastoma

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