Research projects

The following are all current UCLA Brain SPORE research projects.

Project 1

Targeting Immunotherapy-induced Resistance with DC Vaccination and Immune Modulation

The overall goals of this project are to investigate mechanisms of immune evasion following treatment with dendritic cell (DC) vaccines, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment.

We previously found that, in addition to inducing T-cell infiltration into brain tumors, DC vaccination + anti-PD1 blockade may also create a pro-inflammatory environment within the tumor that induces the immigration of immunosuppressive myeloid cells (TIM). TIM are phenotypically similar to the myeloid cells that attenuate the T-cell response to chronic viral infections, and may counteract the anti-tumor T-cell responses induced by DC vaccination. Therapies that target myeloid cells within the tumor microenvironment represent a promising new strategy. As such, inhibition of these myeloid cells using a CSF-1R inhibitor, in conjunction with autologous tumor lysate-pulsed DC vaccination (ATL-DC) and PD-1 mAb blockade, resulted in significantly prolonged survival in tumor-bearing animals with large, well-established intracranial gliomas.

Our hypothesis is that myeloid cells mediate adaptive immune resistance in response to T-cell activation induced by immunotherapy. We have planned a series of novel pre-clinical studies to re-polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor.

• Aim 1: To identify the optimal timing and sequence by which immunotherapy alters the local tumor-infiltrating immune response in syngeneic murine glioma models and in recurrent glioblastoma patients.
• Aim 2: To conduct a new first-in-human Phase I clinical trial of ATL-DC vaccination in conjunction with CSF-1R inhibitor (PLX3397) and PD-1 mAb (Pembrolizumab) blockade, and develop predictive immunological and imaging biomarkers.
• Aim 3: To elucidate the immunotherapy-induced resistance mechanisms by which immuno-suppressive myeloid cells inhibit anti-tumor immune responses in pre-clinical animal models and in newly diagnosed glioblastoma patients.

Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.

Project 2

Overcoming Drug-induced Resistance to Intrinsic Apoptosis in Glioblastoma

Glioblastoma (GBM) tumors are defined by high resistance to therapy-induced cell death. Through a combination of molecular and functional profiling of the intrinsic apoptotic machinery, we have identified that all GBM are comprised of two molecular intrinsic apoptotic blocks – MCL-1 and BCL-xL – to prevent tumor cell death. The goal of Project 2 is to translate rationally-designed drug combinations, consisting of new and pre-existing clinical agents, that selectively ablate the GBM dual apoptotic barrier to promote tumor cell death and induce durable clinical responses in patients.

• Aim 1: To investigate whether a novel, antibody drug conjugate with a potent warhead against an essential apoptotic block has anti-tumor effects when combined with TMZ/radiation or a new, clinical brain penetrant EGFR TKI in pre-clinical GBM models.
• Aim 2: To conduct a “window of opportunity” clinical trial to explore whether these new clinical drugs can ablate the two intrinsic apoptotic blocks in recurrent GBM patients.
• Aim 3: To identify potential mechanisms of resistance to targeting the intrinsic apoptotic machinery in diverse pre-clinical GBM samples.

Together, the studies proposed in this application present a new therapeutic paradigm through specific manipulation of intrinsic apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.

All GBM have a dual apoptotic barrier – MCL1 and BCL-xL. Drug perturbations remove the MCL1 block in a genotype specific manner, creating an exclusive dependency on BCL-xL for survival. For EGFR TKI, changes in FDG uptake is a surrogate for ablation of MCL1.

Project 3

Strategies Against Radiation-induced Cellular Plasticity in Glioblastoma

The overarching goal of Project 3 is to improve radiotherapy (RT) outcome for patients suffering from glioblastoma (GBM). In our last SPORE funding period, we used patient-derived glioblastoma cell lines, patient-derived orthotopic xenografts (PDOXs), and dopamine receptor antagonists (DRAs) to understand how glioma cells react to the combination of radiation and dopamine receptor inhibition. We found that the combination of RT with DRAs upregulated the fatty acid/cholesterol biosynthesis pathway, and that blocking this pathway led to markedly increased survival in tumor-bearing mice. We therefore hypothesize that blocking the radiation-induced phenotype conversion of non-stem GBM cells into radiation-resistant glioma-initiating cells using the dopamine receptor antagonist quetiapine (QTP) and statins improves radiation responses, generates an exploitable metabolic vulnerability, and can be safely applied in patients with recurrent glioblastoma.

Aim 1: To optimize the timing, sequence, and bioavailability of combination treatment with RT/QTP and statins that induces alterations in lipid metabolism and extends survival in tumor-bearing animal models

Aim 2: To test if RT/QTP induces changes in lipid metabolism that can lead to a vulnerability to be targeted for therapeutic gain in a first-in-human combination Phase I clinical trial of RT/QTP +/- statins

Aim 3: To determine the mechanisms by which RT/QTP-induced changes in lipid metabolism may be reversed by statins and prolong survival

Compared to radiation treatment alone, a combination of radiation and the dopamine receptor antagonist quetiapine significantly improves the median survival in mouse models of glioblastoma. At the same time, this combination treatment up-regulates gene expression of key enzymes in the mevalonate pathway with subsequent up-regulation of cholesterol biosynthesis. Targeting the rate-limiting enzyme in the mevalonate pathway, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), using the statin simvatstain down-regulates cholesterol biosynthesis in glioma cells. A triple combination of radiation, quetiapine and simvastatin further improves median survival in mouse models of glioblastoma.

Seed Grant programs