Valganciclovir as Add-on to Second Line Therapy in Patients with Recurrent Glioblastoma

IntroductionGlioblastoma invariably recurs despite aggressive and multimodal first line treatment and no standardized second line therapy exists. We previously reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged overall survival in 102 patients with newly diagnosed glioblastoma. Here we present the results of retrospective survival analyses including patients with glioblastoma that initiated valganciclovir therapy after recurrence. MethodsBetween April 13, 2007 and March 31, 2021, 29 patients with recurrent glioblastoma received valganciclovir as an add-on to second line therapy. Contemporary controls were 111 patients with glioblastoma who received similar second line therapy at our institution. We retrospectively analyzed survival data of these patients. ResultsPatients with recurrent glioblastoma who received valganciclovir had longer median overall survival after recurrence than controls (12.1 vs 7.4 months, respectively, p=0.0017). The drug was well tolerated. Both patients who underwent re-operation and patients that were not re-operated after recurrence benefitted significantly from valganciclovir therapy. Valganciclovir prolonged survival after recurrence both in patients with an unmethylated or methylated MGMT promoter gene. ConclusionValganciclovir was safe to use and prolonged median survival after recurrence of patients with recurrent glioblastoma, re-operated or not after recurrence and with methylated or unmethylated MGMT promoter gene.

Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5β1 Integrin

Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5β1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5β1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5β1 integrin.

Anlotinib Combined with Temozolomide Therapy for Recurrent Glioblastoma (IDH-wt and TERTp-mut) After Standard Treatment

Purpose IDH1-wt glioblastoma patients with TERTp-mut had the worst prognosis, and no effective management strategy was established after tumor recurrence. The median overall survival (OS) of recurrent GBM patients who only received supportive therapy was approximately 1.0 month. We reported survival outcomes of recurrent glioblastoma (rGBM) treated with anlotinib combined with temozolomide therapy (ACTT), and to explore the management strategy of rGBM. Methods The clinical data of 14 rGBM patients treated with ACTT was collected. Therapeutic efficacy and adverse effects were evaluated in every 2 months of treatment. We also included 16 patients treated with bevacizumab (Bev), 22 with TMZ, 28 with re-operation, 21 with re-irradiation, and 75 with supportive care to make comparison. Kaplan-Meier analysis was used to compare the survival of ACTT group versus other treatment groups. Results Fourteen rGBM patients treated with ACTT were enrolled. After 2-month of ACTT, the overall response and disease control rate were 50.0% and 92.9%, respectively. The 6-months PFS rate was 78.6%, and the 1-year survival rate was 50.0%. The median PFS and OS in ACTT group were 11.0 and 13.0 months, respectively. The median PFS and OS in Bev-group was 4.0 and 8.0 months. The patients treated with ACTT had better PFS than that in Bev-group. And compared to all the others treatment groups, ACTT could prolong survival. Conclusion The treatment regimen of ACTT maybe reliable, safe, and effective for rGBM. The patients can gain survival benefits from ACTT, and prolonged survival were observed compared with other treatment regimens.

Compassionate use of recombinant human IL-7-hyFc as a salvage treatment for restoring lymphopenia in patients with recurrent glioblastoma

Purpose Lymphopenia is frequently observed and is associated with poor prognosis in glioblastoma (GBM) patients. Restoring lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin-7 (IL-7) is necessary for proliferation of lymphocytes and to amplify the total lymphocyte count (TLC), IL-7 therapy has been tried for various cancers, although the results are inconclusive. Here, we describe the clinical results of recurrent GBM treated with long-acting engineered version of recombinant human IL-7 (rhIL-7-hyFc). Methods This prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Patients with recurrent GBM were enrolled to Seoul St. Mary's Hospital. Primary outcomes were the safety profile and elevated total lymphocyte count (TLC). Secondary outcomes were overall survival (OS) and progressionbfree survival (PFS). The duration of median follow up was 372.6 days (range 98-864 days). Results Among 18 patients enrolled, 10 received rhIL-7-hyFc with temozolomide, 5 received rhIL-7-hyFc with bevacizumab, 1 received rhIL-7-hyFc with PCV chemotherapy, and 2 received rhIL-7-hyFc alone. The mean TLC of enrolled patients after the first treatment with rhIL-7-hyFc was significantly increased from 1,131 cells/mm^3 (range 330-2,989) at baseline to 4,356 cells/mm^3 (range 661-22,661). Similar increase was observed in 16 of 18 patients (88.8%), only after the first treatment of rhIL-7-hyFc. TLCs of these patients were maintained higher while rhIL-7-hyFc was repeatedly administered. Most common adverse events were injection sites reactions (64.7%) including urticaria and itching sensation, however, there were no serious adverse events more than grade III. Median OS and PFS were 378 days (range 107-864 days) and 231 days (55-726 days), respectively. Conclusion Our study first reports that IL-7 immunotherapy can restore lymphopenia and maintain TLC with various salvageable chemotherapies in recurrent GBM patients without serious adverse toxicities. This outcome warrants further larger and randomized clinical trials to validate the clinical benefits of rhIL-7-hyFc for GBM patients.

Contrast Enhancing Pattern on Pre-Treatment MRI predicts Response to Anti-Angiogenic Treatment in Recurrent Glioblastoma: Comparison of Bevacizumab and Temozolomide Treatment

Objective: To evaluate the value of the contrast enhancing pattern on pre-treatment MRI for predicting the response to anti-angiogenic treatment in patients with IDH-wild type recurrent glioblastoma.Methods: This retrospective study enrolled 65 patients with IDH wild-type recurrent glioblastoma who received standard therapy and then received either bevacizumab (46 patients) or temozolomide (19 patients) as a secondary treatment. The contrast enhancing pattern on pre-treatment MRI was visually analyzed and dichotomized into contrast enhancing lesion (CEL) dominant and non-enhancing lesion (NEL) dominant types. Quantitative volumetric analysis was used to support the dichotomization. The Kaplan-Meier method and Cox proportional hazards regression analysis were used to stratify progression free survival (PFS) according to the treatment in the entire patients, CEL dominant group, and NEL dominant group.Results: In all patients, the PFS of those treated with bevacizumab was not significantly different from those treated with temozolomide (log-rank test, P=.96). When the contrast enhancing pattern was considered, bevacizumab was associated with longer PFS in the CEL dominant group (P=.031), whereas temozolomide showed longer PFS in the NEL dominant group (P=.022). Quantitative analysis revealed cut-offs for the proportion of solid-enhancing tumor of 13.7% for the CEL dominant group and 4.3% for the NEL dominant group. Conclusions: Patients with the CEL dominant type showed a better treatment response to bevacizumab, whereas NEL dominant types showed a better response to temozolomide. The contrast enhancing pattern on pre-treatment MRI can be used to stratify patients with IDH wild-type recurrent glioblastoma according to the effect of anti-angiogenic treatment.

Comparison of Tumor Immune Environment Between Newly Diagnosed and Recurrent Glioblastoma in Matched Patients

Purpose: Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment (TME), especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined. Methods: To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients’ GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions. Results: We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs and macrophages at initial diagnosis did not correlate with OS. TILs and macrophages were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with worse prognosis, respectively. Conclusion: Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.

Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVAglio ancillary study

We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34–0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils.