Cellular and Targeted Therapies Fuel Hope in Brain Malignancies

Murali Chintagumpala, MD

Codirector, Brain Tumor Program

Texas Children’s Hospital

Professor Department of Pediatrics

Section of Hematology/Oncology

Baylor College of Medicine

Houston, TX

Brain tumor therapy traditionally consists of surgery, radiotherapy (RT), and chemotherapy. Outcomes are suboptimal and even dismal for certain tumors, and adverse events associated with these therapies are substantial. However, increased understanding of the tumor microenvironment, the importance of molecular abnormalities, and the signaling pathways of cytokines has finally yielded more effective, tumor-specific therapies.

Important prognostic factors in gliomas are alterations in the BRAF, IDH1, and IDH2 genes as well as genomic 1p/19q codeletion. Whereas medulloblastoma, the most frequent embryonal tumor, is divided into 4 molecularly defined groups: Wnt signaling pathway activated, Shh signaling pathway activated and TP53 mutated, Shh activated and TP53 wild type, and non-Wnt/ non-Shh activated.^1,2 Genome-wide methylation profiling has also become a promising new tool in central nervous system tumor diagnostics; MGMT promoter methylation and concomitant inactivation of the DNA repair enzyme activities may predict the response to agents such as temozolomide (TMZ; Temodar). Detailed analysis of the molecular structure of the tumor is thus very important.

“The specialized laboratory at a brain tumor research center can help the community oncologist by offering DNA and RNA sequencing as well as proteomics and methylation analysis. This will allow the practitioner to choose the most appropriate treatment according to the tumor profile,” Murali Chintagumpala, MD, said in an interview with Targeted Therapies in Oncology. Chintagumpala is codirector, Brain Tumor Program at Texas Children’s Hospital and professor of pediatrics at Baylor College of Medicine, both in Houston.

Immunotherapy is another promising approach, although overcoming the blood-brain barrier and the heterogeneity of certain tumors, such as glioblastoma (GBM; grade 4 astrocytoma), represents a challenge. Trials using immune checkpoint inhibitors, oncolytic viruses, or nonreplicating viral vectors as well as chimeric antigen receptor (CAR) T-cell therapy may soon change the outcomes for patients with brain tumors.³ Trials are ongoing in both adult and pediatric patients.⁴

Glioblastoma Multiforme

Standard management of GBM includes maximal safe surgical resection, RT, and chemotherapy with TMZ (the Stupp protocol), but participation in a clinical trial is highly recommended because the 5-year survival rate is less than 10%.^5,6 Tumors with MGMT gene promoter methylation have a better response to TMZ, but relapse is still highly likely, and unlike lower-grade gliomas, IDH gene mutations are rare.⁷ None of the current therapies represent breakthroughs, but research is more focused on understanding the microenvironment of tumors that could explain the lack of activity of many approaches.

Immune Checkpoint

Inhibitors Immune checkpoint inhibitor therapies against PD-1/PD-L1 or CTLA-4 have been successful in many different tumors but have yielded disappointing results when used as monotherapy in GBM.⁸ Findings from recent studies observed the expression of PD-L1 in more than 80% of newly diagnosed GBM and 72% of recurrent GBM. Some current monoclonal antibodies that have been investigated are nivolumab (Opdivo), pembrolizumab (Keytruda), cemiplimab (Libtayo; targeting PD-1), durvalumab (Imfinzi), avelumab (Bavencio), atezolizumab (Tecentriq; targeting PD-L1), and ipilimumab (Yervoy; targeting CTLA4).^8,9 Although monotherapy has limited activity, combination trials may yield better results.

Selinexor

Selinexor (Xpovio) is an oral selective inhibitor of exportin (XPO1) that passes the blood-brain barrier. XPO1 is an export receptor responsible for the nucleocytoplasmic transport of many proteins and RNA species and is frequently overexpressed and/or mutated in human cancers. Its inhibition causes nuclear retention and functional reactivation of tumor suppressor proteins, reduces translation of oncogene mRNAs, impairs DNA repair, and causes apoptosis.¹⁰

A phase 2 trial of 76 patients with recurrent GBM evaluated selinexor monotherapy. Patients undergoing cytoreductive surgery received up to 3 selinexor doses twice weekly during the preoperative phase, with the goal of assessing intratumoral pharmacokinetics and pharmacodynamics. Patients not undergoing surgery received 50 mg/m² (Arm B; n = 24), 60 mg twice weekly (Arm C; n = 14), or 80 mg once weekly (Arm D; n = 30). The progression-free survival (PFS) rates at 6 months were 10%, 7.7%, and 17.2% for Arms B, C, and D, respectively, and a measurable reduction in tumor size was observed in 28% of patients overall (TABLE).¹¹ The most common hematological toxicities were thrombocytopenia (43.4%), neutropenia (26.3%), and anemia (17.1%), and the most common nonhematological treatment- related adverse events (TRAEs) were fatigue (60.5%), nausea (59.2%), and decreased appetite (43.4%). A combination trial with TMZ and RT in newly diagnosed patients is currently underway (NCT04216329).

Glasdegib

Glasdegib (Daurismo) is a novel hedgehog signaling pathway inhibitor that may disrupt glioma stem cell maintenance. Patients with newly diagnosed GBM received glasdegib with standard RT/TMZ followed by maintenance with glasdegib monotherapy (GEINOGLAS; NCT03466450). Stabilization at the 75-mg dose level was the most common response, reported in 81.1% of patients. The median PFS was 6.9 months, with a PFS rate at 6 months of 62.1% and an overall survival (OS) at 18 months of 63.3%. Fewer than 10% of patients had hematological TRAEs of grade 3 or above, and none occurred during the monotherapy maintenance phase.¹²

Anlotinib

The addition of anlotinib, a multitarget tyrosine kinase inhibitor, to RT/TMZ for newly diagnosed glioblastoma was studied in 33 patients in China (NCT04119674). All patients received RT for 6 weeks with concurrent oral TMZ and anlotinib. After a 28-day treatment break, adjuvant therapy was started with 6 cycles of TMZ and 8 cycles of anlotinib, followed by anlotinib monotherapy until disease progression or intolerable toxicities. Results of the trial showed a median PFS of 10.9 months and OS of 18.7 months, with impressive results maintained after 1 year (PFS of 45.5% and OS of 72.7%). Three patients (9.1%) had grade 3 or 4 thrombocytopenia and 1 patient (3.0%) had grade 3 vomiting during adjuvant therapy, but no AEs of grade 3 or above were observed during the concurrent phase or anlotinib maintenance phase.¹³

D2C7 Immunotoxin

Immunotoxins are an exciting new therapy for brain tumors. When immunotoxins are injected directly into the tumor by convection-enhanced delivery (CED), they induce both direct tumor killing and secondary immune responses through the activation of CD4-positive and CD8-positive T cells.

D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin of an EGFR wild-type and mutation-specific (EGFR variant III) monoclonal antibody fragment. D2C7-IT binds to EGFR followed by cellular internalization, and the Pseudomonas exotoxin moiety of the D2C7-IT kills residual GBM cells and upregulates pro-inflammatory CD40. This potentially creates a proinflammatory glioma microenvironment where the activation of tumor-associated macrophages may be further stimulated by sequential CED of 2141-V11, an Fc-engineered antihuman CD40 agonist antibody. Intratumoral administration of D2C7-IT plus 2141-V11 via CED was shown to be safe in 3 patients, and early efficacy results were observed.¹⁴

Vaccine Therapy

The goal of vaccine therapy is the induction of the patient’s own adaptive immune response, which stimulates immunogenicity against cancer cells.¹⁵ There are 3 main approaches in vaccine therapy against GBM: tumor-specific antigens, cell-based therapies as dendritic cells, and viral vector vaccines transporting tumor antigens as mRNA.

ICT-107 is an autologous, monocyte- derived, dendritic cell vaccine that targets 6 tumoral antigens, including HER2/ neu, TRP-2, MAGEA1, gp100, AIM2, and IL-13Rα2. In a double-blind, randomized phase 2 trial in patients with newly diagnosed GBM, the PFS was greater by 2.2 months in the ICT-107 cohort (P = .011), but although the median OS was also better in the ICT-107 group by 2 months, this was not statistically significant.¹⁶

Autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) with standard-of-care therapy was studied in a phase 3 trial of patients with newly diagnosed or recurrent GBM (NCT00045968). The OS for patients with newly diagnosed GBM was 19.3 months compared with 16.5 months in historical controls; in patients with recurrent GBM, the OS was 13.2 months vs 7.8 months. DCVax-L was well tolerated, and there was no evidence of any autoimmune reactions or cytokine storm.¹⁷

Oncolytic Virus Therapy

Oncolytic virus (OV) therapy uses several mechanisms of action, including the release of tumor antigens and damage-associated molecular patterns, inhibition of tumoral immunosuppressive genes, transport of proinflammatory agents to tumoral cells, and tumoral microenvironmental disruption.⁹ They selectively damage cancer cells through the inherent affinity of some viral receptors in the tumor cell surface. OVs are attenuated strains or strains that can infect and replicate in humans without causing any serious disease, and they can be based on different viruses, such as herpes simplex virus, adenovirus, poliovirus, parvovirus, and measles^.18 Preclinical data and reports of small numbers of patients are promising.^19,20

CAR T-Cell Therapy

The field of CAR T-cell therapies is moving rapidly. One major problem is the need for autologous cells, which creates a delay in starting the therapy. Thus, the creation of products that are off the shelf is now being evaluated, including in GBM.

Based on the results of a trial with autologous cells, a healthy donor–derived, IL-13Rα2–targeted CAR T-cell product was genetically engineered to permanently disrupt the glucocorticoid receptor GRm13Z40-2 and endow resistance to glucocorticoid treatment. These allogeneic GRm13Z40-2 T cells in combination with intracranial recombinant human IL-2 were administered in a phase 1 safety and feasibility trial to 6 patients with unresectable recurrent GBM. The treatment was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T-cell infusion in 4 of the 6 patients.^21,22

Another trial evaluated the infusion of GD2-specifi c fourth-generation safety- designed CAR (4SCAR) T cells in 8 patients with GBM (NCT03170141). Four of the 8 evaluable patients showed a partial response for 3 to 24 months, 3 had progressive disease for 6 to 23 months, and 1 had stable disease for 4 months after infusion. For the entire cohort, the median OS was 10 months from the infusion.²³

Low- and Intermediate-Grade Gliomas

IDH gene mutations are recognized as an oncogenic driver in gliomas, are associated with significantly improved survival, and are the target of some very promising new therapies.²⁴ IDH mutations are especially prevalent in lower-grade tumors (present in more than 68%), with a preponderance of IDH1 over IDH2 mutations (95:5).²⁵ Intratumoral levels of 2-hydroxyglutarate (2HG), which is produced at high levels in tumors with mutated IDH1 (mIDH1), decrease within 1 week of management with IDH1 inhibitors, as shown by noninvasive 3-dimensional magnetic resonance spectroscopic imaging.²⁶

According to David Reardon, MD, clinical director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, Massachusetts, this is one of the most exciting developments in the treatment of patients with grade 2 and 3 gliomas. “Seventy [percent] to 80% of these patients have mutations in the IDH gene, primarily IDH1, and this has led to an explosion of research geared toward the understanding of the biology of these tumors and the development of therapies that have a meaningful impact on the outcomes of these patients,” Reardon said in an interview with Targeted Therapies in Oncology. Two drugs are especially noteworthy: vorasidenib (AG-881) and ivosidenib (Tibsovo).

David Reardon, MD

Clinical Director

Center for Neuro-Oncology

Institute Physician

Dana-Farber Cancer Institute

Professor of Medicine

Harvard Medical School

Boston, MA

Ivosidenib

Ivosidenib is an mIDH1 inhibitor that was approved by the FDA for hematologic malignant diseases, such as acute myeloid leukemia and cholangiocarcinoma.²⁷ In a multicenter, open-label, phase 1, dose- escalation and dose-expansion study of ivosidenib in 66 patients with mIDH1 and advanced gliomas, ivosidenib was given orally at 500 mg every day in 28-day cycles. In patients with measurable disease at baseline, tumor measurements decreased from baseline in 22 of 33 nonenhancing tumors (66.7%) and 9 of 27 enhancing tumors (33.3%). Most patients had stable disease (85.7% with nonenhancing tumors and 45.2% with enhancing tumors), and the median PFS was 13.6 months and 1.4 months, respectively. The treatment was well tolerated, with 19.7% of patients experiencing AEs of grade 3 or above but only 3% experiencing TRAEs.²⁸

Vorasidenib

Vorasidenib is a first-in-class, brain- penetrant, dual inhibitor of the mutated IDH1 and IDH2 enzymes. A multicenter, dose-escalation study (NCT02481154) enrolled 52 patients with mIDH1/2 gliomas that had recurred or progressed following standard therapy. The objective response rate in patients with nonenhancing glioma was 18%. The median PFS was 36.8 months for patients with nonenhancing glioma and 3.6 months for patients with enhancing glioma. The safety profile was characterized by reversible dose-limiting toxicities of elevated transaminases at doses of 100 mg or greater.²⁹ Results from a phase 3 placebo-controlled study (INDIGO; NCT04164901) are expected to be released soon.

“In our experience, a significant number of patients treated with these drugs achieve durable responses, lasting even for years, including a subset of them with radiographic responses,” Reardon said. “I have patients who have been on ivosidenib for 5 years. The other great thing about these drugs is the fact that [AEs] are minimal in contrast [with] our standard approaches with chemotherapy, surgery, and radiation.”

The activity of both drugs has also been measured directly in tumor tissue. The concentration of 2HG, the metabolic product of mutated IDH enzymes, was measured in tumor tissue from 49 patients with mIDH1 nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily), ivosidenib (500 mg daily or 250 mg twice daily), or no treatment before surgery. The concentrations of 2HG in the tumors were reduced by 92.6% and 91.1% in patients treated with vorasidenib 50 mg daily and ivosidenib 500 mg daily, respectively.³⁰

“There is a new paradigm in clinical research in using neoadjuvant clinical trials, so-called window-of-opportunity trials, in which patients who are scheduled for planned surgery receive a study drug for 10 to 14 days before the surgery,” Reardon said. “After resection of the tumor, the tissue is evaluated for the pharmacokinetics and pharmacodynamics of the study drug, which helps to prioritize which drugs to evaluate in further clinical trials.”

In summary, the field of brain tumor research has made immense progress. The insights gained are now finally resulting in drugs that can change the outcomes for patients.

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