‘Cold’ glioblastoma tumors require combination therapies to improve response rates, says GlobalData

New Delhi: With only a small percentage of patients with glioblastoma multiforme (GBM) showing a benefit from immune checkpoint inhibitors, drug developers must focus on combination therapies to improve response rates, according to GlobalData, a leading data and analytics company.

GBM is the most common form of grade IV brain cancer and considered to be one of the most ‘immune-cold’ tumors relative to other cancers, which limits the effectiveness of immunotherapies. ‘Cold’ verses ‘hot’ refers to how densely the tumors are infiltrated by the immune system’s army of cells.

Mr Ashwin Oberoi, Healthcare Analyst at GlobalData, remarked: “In general, cold GBM tumors have very few T-cell infiltrates, and those within the tumor are scattered. Additionally, GBM tumors are considered to have one of the lowest rates of tumor mutation burden (TMB), a measure of the number of mutations in a tumor genome, relative to other cancers. This is believed to result in fewer cancer-specific ‘neoantigens’ and poor immunogenicity of the tumor, thus leading to poor responses to immunotherapy.”

Following the early termination in April 2017 of Bristol-Myers Squibb’s (BMS’s) Phase III trial CheckMate 143, which evaluated Opdivo monotherapy for patients with recurrent GBM, there has been an increased effort to reassess research and development strategies.

The CheckMate 143 trial failure suggests that targeting newly diagnosed GBM patients with combinations of immunotherapies may offer a greater benefit. More evidence has been released that GBM tumors become even more immunosuppressive once the tumors recur, especially with first-line treatment of temozolomide. Therefore, targeting the newly diagnosed (temozolomide naïve) GBM patient population could be a more effective strategy.

A second method to improve response rates in patients could be to increase T-cell infiltration into the tumor, for example by combining immune-checkpoint inhibitors with vaccines to activate these immune-cold tumors. If antigen-specific T-cells have been induced, this could potentially force T-cells into the tumor, leading to warmer tumors and more significant responses for GBM patients. BMS currently has two ongoing trials of Opdivo with radiotherapy and with and without temozolomide for patients with newly diagnosed GBM, named CheckMate-498 and CheckMate-548.

Oberoi concludes: “Ultimately, the use of immune-checkpoint inhibitors as a monotherapy is observed to be limited for patients with immune-cold GBM tumors. A two-pronged strategy, featuring combinations with other treatment modalities, such as radiotherapy, or with other immune-related therapies such as oncolytic viruses or DNA vaccines, coupled with targeting the newly diagnosed GBM patient population, may lead to more promising outcomes for patients with this highly aggressive form of brain cancer.”