Monoclonal Antibody Treatment in Newly Diagnosed Pediatric High-Grade Glioma

Excerpt:

“In a phase II study reported in the Journal of Clinical Oncology, Grill et al found that the addition of bevacizumab (Avastin) to radiotherapy plus temozolomide (RT + TMZ) did not improve event-free survival in pediatric patients with newly diagnosed high-grade glioma.

“In the international open-label study, 121 patients aged 3 to 18 years with localized nonbrainstem disease from 51 sites in 14 countries were randomized between October 2011 and February 2015 to receive RT + TMZ with (n = 62) or without (n = 59) bevacizumab 10 mg/kg every 2 weeks. RT + TMZ consisted of RT at 1.8 Gy 5 days per week and TMZ at 75 mg/m2 per day for 6 weeks followed by a 4 weeks off, then up to twelve 28-day cycles at 150 mg/m2 per day on days 1 to 5 in cycle 1 and 200 mg/m2 per day on days 1 to 5 in cycles 2 to 12. The primary endpoint was event-free survival on blinded central radiology review. Results are reported as of 12 months after the enrollment of the last patient.”

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Targeting Integrin β3-Src Pathway May Be Potential Strategy for Overcoming Anti-IGF-1R Antibody Resistance

Clinical trials have shown limited efficacy of anti–insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies, with the mechanisms of resistance to IGF-1R monoclonal antibody-based therapy remaining undefined. In preclinical studies reported in the Journal of the National Cancer Institute, Dong Hoon Shin, of The University of Texas MD Anderson Cancer Center and colleagues found that the integrin β3-Src signaling cascade and thus Akt were activated by IGF-1 when IGF-1 binding was inhibited by the anti-IGF-1R monoclonal antibody cixutumumab and that targeting integrin β3 or Src resulted in enhanced antitumor activity of cixutumumab in resistant cell lines and xenografts.


Depleting Tumor-Specific Tregs at a Single Site Eradicates Disseminated Tumors

“Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40.”


Depleting Tumor-Specific Tregs at a Single Site Eradicates Disseminated Tumors

“Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40.”


Depleting Tumor-Specific Tregs at a Single Site Eradicates Disseminated Tumors

“Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40.”


Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

“As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti-PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti-CD137 (urelumab), anti-OX40, anti-GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important.”