TIL therapy: 6 things to know
Jason Bock, Ph.D., vice president of Therapeutics Discovery and head of Biologics Development, speaks to Cancerwise about tumor-infiltrating lymphocytes (TILs) and how this experimental cell therapy is being developed to treat solid tumors.
The University of Texas MD Anderson Cancer Center and Boehringer Ingelheim today announced the extension and expansion of their joint Virtual Research and Development Center (VRDC) to explore new molecules from Boehringer Ingelheim’s KRAS (Kirsten rat sarcoma) and TRAILR2 (TNF-related apoptosis-inducing ligand receptor 2) portfolios for the potential treatment of lung cancer, particularly non-small cell lung cancer.
The collaboration, launched in 2019, has successfully combined MD Anderson’s innovative clinical research infrastructure and the patient-driven drug development capabilities of the Therapeutics Discovery division with Boehringer Ingelheim’s pipeline of innovative cancer medicines and expertise in advancing breakthrough therapies. Under the new agreement, joint research will continue for five additional years.
“Our collaboration with MD Anderson strengthens our determination to find solutions for the most difficult-to-treat cancers, and this latest commitment marks an important step forward, especially in our holistic KRAS program,” said Norbert Kraut, Ph.D., head of Global Cancer Research at Boehringer Ingelheim. “We are delighted to extend our collaboration with MD Anderson. With our shared dedication to patients and like-minded approach to innovation, we have the potential to bring the medicines to lung and gastrointestinal cancer patients that they so much need.”
The flexible nature of the VRDC agreement allows the teams to expand their lung cancer indication programs targeting KRAS and TRAILR2, including Boehringer Ingelheim’s first-in-class SOS1::pan-KRAS inhibitor (BI 1701963), inhibitors of KRAS G12C (BI 1823911) and MEK (BI 3011441), as well as a novel undisclosed bi-specific TRAILR2 agonist.
The collaboration already has resulted in a number of joint publications, conference presentations (including at the 2021 AACR Annual Meeting) and clinical trial activities. Boehringer Ingelheim is pursuing a comprehensive mutant KRAS-directed effort with multiple programs expected to enter the VRDC with MD Anderson.
“We are proud to expand our work with Boehringer Ingelheim in a very exciting drug-development space – advancing novel targeted therapies against KRAS and TRAILR2,” said Timothy Heffernan, Ph.D., head of oncology research in Therapeutics Discovery at MD Anderson. “Our collaboration is built upon a strong working relationship and complementary expertise, highlighting how an academic center and a pharmaceutical company can strategically work together to advance innovative therapies for patients with cancer.”
MD Anderson’s Therapeutics Discovery division is anchored by an experienced team of drug development experts working to advance the next generation of cancer therapies. The Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, led by Heffernan, performs cutting-edge translational research to rapidly advance new therapies to the patients most likely to benefit.
KRAS is the most frequently mutated cancer-causing oncogene. One in seven of all human metastatic cancers expresses KRAS mutations, with mutation rates of more than 30 percent in lung adenocarcinomas, more than 40 percent in colorectal cancers and more than 90 percent in pancreatic cancers. No approved treatments for KRAS-driven cancers exist currently, further underscoring the need for continued investment in research and development. Tumor cell-selective activation of TRAILR2 can trigger cancer cell death in indications of high medical need, including lung and gastrointestinal malignancies.
MD Anderson has an institutional financial conflict of interest with Boehringer Ingelheim related to this research and has therefore implemented an Institutional Conflict of Interest Management and Monitoring Plan.
A preclinical study led by researchers at The University of Texas MD Anderson Cancer Center shows an antibody-drug conjugate (ADC) targeting surface protein MT1-MMP can act as a guided missile in eradicating osteosarcoma tumor cells without damaging normal tissues. This technology, using precision therapy targeting of cell-surface proteins through a Bicycle toxin conjugate (BTC), shows encouraging results for the treatment of osteosarcoma.
Findings from the study were presented today by Yifei Wang, M.D., a postdoctoral fellow of Pediatrics Research, at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021. The study was led by Richard Gorlick, M.D., chair and division head of Pediatrics.
Osteosarcoma is the most common type of bone tumor in adolescents and young adults. The outcome of patients with osteosarcoma has not improved in the last several decades ― since the implementation of adjuvant chemotherapy. For patients who are unable to tolerate the side effects of chemotherapy, few alternative treatments are available. While novel immunotherapies have shown promising efficacy in hematologic malignancies, like leukemia and lymphoma, little progress has been made in recent years for osteosarcoma.
“It’s a novel approach for osteosarcoma and we now have the opportunity to explore new treatment options,” Gorlick said. “This discovery represents a paradigm shift that will help us to move forward more rapidly. I anticipate that there will be an influx of other drugs that can be tested, and because the drugs are targeted to a particular surface protein, they are potentially more effective and have fewer side effects.”
In this study, researchers developed an integrated bioinformatic approach using proteomic and transcriptomic data compiled from the profiling data of osteosarcoma cell lines, mouse models, hundreds of patient tumor samples and thousands of normal human tissues. This approach identified surface proteins that are highly expressed on the osteosarcoma cell surface, but not in the normal tissues. Results from the analytical laboratory technique confirmed specific proteins could be targeted therapeutically by ADC or BTC.
The team had previously identified four surface proteins, MT1-MMP, MRC2, CD276 and LRRC15, that were highly expressed on the cell surface of osteosarcoma, but not in the normal human tissues. An earlier evaluation of CD276 and LRRC15 targeted ADC showed encouraging antitumor activity, validating the research team’s approach.
In this study, researchers focused on MT1-MMP as a drug target, validating the expression of the target in patient samples. They then tested an MT1-MMP targeted BTC, BT1769, in preclinical osteosarcoma mouse models. The drug proved to be highly active in the preclinical test, with 50% of the mice showing a 100% improved response.
“We are excited by these results because this target and drug have not been previously reported in osteosarcoma,” Wang said. “This is the first in a series of other proteins that have been identified by the same method.”
If successful in clinical trials, this research may bring new opportunities for the treatment of osteosarcoma, with higher efficacy and minimal toxicity exposure. Gorlick and his lab also are working with MD Anderson’s Therapeutics Discovery team on new approaches for targeting antibodies.
This work was funded by National Institutes of Health (NIH)/National Cancer Institute (NCI) (5U01CA199221-06), Swim Across America, The Foster Foundation, the Terry Fox Foundation, an Osteosarcoma Institute Translational and Preclinical grant, and the Barbara Epstein Foundation. MD Anderson Cancer Center’s Proteomics Facility was funded in part by NIH/NCI Cancer Center Support Grant (P30CA016672), NIH High End Instrumentation program grant (1S10OD012304-01), and Cancer Prevention and Research Institute of Texas Core Facility Grant (RP130397). NIH/NCI Cancer Center Support Grant (P30CA016672) also supported the Clinical Trials Office and the Bioinformatics Shared Resource.
Early phase clinical trials conducted by researchers from The University of Texas MD Anderson Cancer Center show promising results for patients with RET fusion-positive cancers, high-grade (HGG) and low-grade glioma (LGG) and ovarian cancer.
The results, presented today at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021, showcase the researchers’ ongoing efforts to advance clinical studies and expand potential indications of approved drugs to develop a platform for more effective treatments and to improve patient outcomes.
FDA-approved selpercatinib shows clinical benefits for RET fusion-positive cancers beyond lung and thyroid cancers ( Abstract CT011 )
Clinical trial results of RET kinase inhibitor selpercatinib show that the targeted therapy was effective in preventing or inhibiting the growth of tumors in RET fusion-positive cancers other than lung and thyroid cancers. The results, derived from a cohort of patients enrolled in the phase 1/2 LIBRETTO-001 trial, were presented by Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics.
Selpercatinib became the first treatment approved by the Food and Drug Administration (FDA) to treat RET fusion-positive lung and thyroid cancers, as well as RET-mutant medullary thyroid cancer (MTC), in May 2020. However, because RET alterations also have been shown to be oncogenic drivers in the pathogenesis of other cancers, it was postulated that selpercatinib could be used to treat other advanced solid tumors in which RET alterations occur.
“Selpercatinib demonstrates promising activity across a variety of non-lung and non-thyroid RET fusion-positive advanced solid tumors, including treatment-refractory GI malignancies,” Subbiah said. “Although RET fusions are rare, this undoubtedly has conferred clinical benefit and the gift of time to these patients.”
Thirty-two patients with RET fusion-positive non-lung or non-thyroid cancers participated in the study, representing 12 unique tumor types — including pancreatic, colon, breast, salivary, sarcoma and pulmonary carcinosarcoma. Twenty-nine of the patients were previously treated with systemic therapy.
The objective response rate in this heavily pretreated patient population was 47%, including complete responses observed in two patients. Responses were observed across nine unique cancer types and a spectrum of fusion partners. Responses were ongoing in 73% of the patients, and the median duration of response was not reached at a follow-up of 13 months. The safety profile of this cohort is consistent with the known profile of selpercatinib in the overall LIBRETTO-001 population.
The LIBRETTO-001 trial, which spans 16 countries and 89 sites, continues to enroll patients with RET-altered non-lung cancer.
“These are definitely impactful data for precision oncology from the clinical and translational perspective,” Subbiah emphasized. “These analyses reiterate the importance of broad-based genomic profiling to identify actionable oncogenic drivers, including RET fusions.”
This research was supported by Eli Lilly and Company. A full list of collaborating authors and their disclosures can be found with the abstract.
Combining dabrafenib and trametinib to treat BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) shows significant antitumor activity ( Abstract CT025 )
In a nonrandomized, open-label phase 2 study, MD Anderson researchers showed that the combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib had promising efficacy in patients with BRAF V600 mutation-positive HGG and LGG.
BRAF mutations occur in approximately 3% of glioblastomas and 15% of low-grade gliomas.
The FDA approved a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib, which blocks proteins that facilitate cancer cell growth, to treat patients with BRAF V600-positive melanoma, non-small cell lung carcinoma and anaplastic thyroid cancer.
“Glioblastoma is a very difficult-to-treat tumor and has historically shown resistance to therapies, and this is the first time that a targeted therapy has shown significant activity in these challenging tumors,” said Subbiah, who presented these findings.
The HGG arm of the trial enrolled 45 patients previously treated with radiotherapy, surgery or chemotherapy. A majority of patients had glioblastoma, while the rest had anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma.
After undergoing the combination therapy, patients showed a 33% objective response rate. The tumors continued to respond to treatment without cancer growth or spread for 36.9 months.
While 13 patients were enrolled in the LGG cohort, eight patients — who were previously treated with surgery, radiotherapy and chemotherapy — were evaluated in the study and achieved an objective response rate of 69%. The median duration of response, median progression-free survival and median overall survival rates were not reached.
Among both cohorts, 54 patients (93%) experienced a common adverse event — including fatigue, headache, nausea and fever — and 31 patients (53%) experienced a Grade 3 or greater adverse event — such as fatigue, decreased neutrophil count, headache and neutropenia. No new safety signals were detected.
Ultimately, results from this basket trial show that dabrafenib combined with trametinib achieved meaningful response rates in patients with recurrent gliomas with BRAF V600E mutations, regardless of glioma subtype.
“Molecular screening strategies that include BRAF V600E mutations will be crucial for identifying patients who may benefit from these therapies,” Subbiah said. “We recommend that testing is adopted in clinical practice for patients with glioma.”
This research was supported by Novartis. A full list of collaborating authors and their disclosures can be found with the abstract.
Newly discovered metabolic vulnerability may offer treatment strategy for certain patients with ovarian cancer ( Abstract 87 )
Researchers from MD Anderson’s Therapeutics Discovery division previously reported the discovery and development of IACS-6274, a novel small-molecule inhibitor targeting the metabolic enzyme glutaminase (GLS1). Through a patient-driven translational biology effort, the researchers now have identified and validated asparagine synthetase (ASNS) as a candidate biomarker to predict those most likely to benefit from the therapy.
The new findings were shared in a minisymposium presentation by Nakia D. Spencer, institute associate scientist IV with the Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform and one of the GLS1 project leads.
The development of IACS-6274, previously known as IPN60090, was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and TRACTION platforms, both engines within Therapeutics Discovery. The drug is now under investigation in a Phase I trial for advanced solid tumors.
“Ovarian cancer remains an area of unmet medical need for our patients,” Spencer said. “Utilizing team science to drive patient-focused research, we discovered that ovarian tumors lacking ASNS respond to IACS-6274 treatment, pointing us toward a significant number of patients who may benefit from this therapy.”
Disruptions in normal cellular metabolism are distinguishing characteristics of many cancers, and the GLS1 enzyme is critical to many metabolic processes. In the preclinical development of IACS-6274, TRACTION researchers demonstrated promising activity in certain ovarian cancer preclinical models.
In ovarian cancer cell lines that respond to IACS-6274, treatment disrupts normal metabolism of specific amino acids and antioxidants, resulting in the accumulation of DNA damage and inhibiting tumor growth. By comparing sensitive and resistant cell lines, the researchers discovered that high expression of the metabolic enzyme ASNS predicted resistance to IACS-6274.
These results were confirmed in animal models, where ovarian cancers with low ASNS expression were responsive to IACS-6274 treatment and those with high ASNS expression were not. Working with the Pathology and Laboratory Medicine division, the team created a CLIA-certified assay to quantify ASNS levels in tumor samples.
“Advancing treatments that provide the greatest benefits to patients requires a strong translational and drug discovery package that complements the clinical efforts,” Spencer said. “Applying what we are learning from our ongoing clinical study, we continue to develop multiple biomarker-driven patient stratification strategies to identify those most likely to benefit from IACS-6274.”
Therapeutics Discovery researchers will share additional updates on IACS-6274 development in poster sessions, including the identification of rational combination strategies for GLS1 inhibitors and the effects of IACS-6274 on the antitumor immune response.
The University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division and Orionis Biosciences today announced the launch of Project Helios, a research collaboration designed to unlock new drug development opportunities through genome-scale mapping of drug-target interactions.
Combining Orionis’ unique high-throughput drug discovery technologies with the Therapeutics Discovery division’s expertise in small-molecule therapies and translational biology, Project Helios aims to create an unparalleled collection of drug-target interaction data to enable rational drug discovery, optimization and repurposing. The project will focus initially on developing therapies for unmet needs in oncology, with the possibility of expanding to additional therapeutic areas in the future.
“We are excited to be collaborating with MD Anderson’s Therapeutics Discovery team in launching Project Helios, a fundamental step toward new approaches in drug discovery that will enlighten our understanding of the dark proteome. This effort will build on a wealth of public data, chemical and clinical knowledge that has been assembled over many years across the pharmaceutical industry and biomedical institutions,” said Niko Kley, chief executive officer at Orionis.
Molecular interactions between small-molecule drugs and proteins define both their therapeutic efficacy as well as undesired adverse effects. A comprehensive unraveling of these interactions is fundamentally important both for illuminating new drug development opportunities and devising safer medicines with fewer related toxicities.
“We are pleased to be collaborating with Orionis on this exciting initiative to understand drug-target interactions at a new level of detail. The intersection of the data from Project Helios with the unparalleled translational research and drug discovery capabilities at MD Anderson should yield important insights for therapeutics development, hopefully resulting in impactful new medicines for patients with cancer,” said Philip Jones, Ph.D., vice president of Therapeutics Discovery at MD Anderson.
Project Helios will conduct systematic and unbiased mapping of drug interactions across the human proteome with a large portfolio of bioactive, chemically diverse small molecules, including experimental and approved drugs. The findings may provide opportunities to repurpose approved therapies, optimize therapeutic approaches for known targets and develop therapies for novel targets.
“We expect Project Helios to generate a unique data set for the application of new machine-learning models for multivariate, genomic-scale drug design and to further illuminate what we refer to as the ‘Drug Pocketome’ [small-molecule binding sites on drug targets],” said Riccardo Sabatini, chief data scientist at Orionis.