Soluble immune-checkpoint factors: a potential immunotherapy biomarker.

There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.

The neo-open reading frame peptides that comprise the tumor framome are a rich source of neoantigens for cancer immunotherapy.

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate cancer whole genome and long-read transcript sequencing to identify the collection of novel open reading frame peptides (NOPs) expressed in tumors, termed the framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe an uncharacterized class of hidden NOPs, which derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of non-coding regions of the genome downstream of a rearrangement breakpoint. NOPs represent a vast amount of possible neoantigens particularly in tumors with many (complex) structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T-cells specific for hidden NOPs in lung cancer patient peripheral blood.

Immune Checkpoint Inhibitors in Geriatric Oncology.

PURPOSE OF REVIEW: This manuscript will update prior reviews of immune checkpoint inhibitors (ICIs) in light of basic science, translational, and clinical discoveries in the field of cancer immunology and aging. RECENT FINDINGS: ICIs have led to significant advancements in the treatment of cancer. Landmark trials of ICIs have cited the efficacy and toxicity experienced by older patients, but most trials are not specifically designed to address outcomes in older patients. Underlying mechanisms of aging, like cellular senescence, affect the immune system and may ultimately alter the host's response to ICIs. Validated tools are currently used to identify older adults who may be at greater risk of developing complications from their cancer treatment. We review changes in the aging immune system that may alter responses to ICIs, report outcomes and toxicities in older adults from recent ICI clinical trials, and discuss clinical tools specific to older patients with cancer.

Use, access, and initial outcomes of off-label ivosidenib in patients with IDH1 mutant glioma.

Background: Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Methods: Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. Results: The cohort age range was 21-74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Conclusions: Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.

Clinical Management of Patients with Non-Small Cell Lung Cancer, Brain Metastases, and Actionable Genomic Alterations: A Systematic Literature Review.

INTRODUCTION: Nearly 60% of patients with non-small cell lung cancer (NSCLC) present with metastatic disease, and approximately 20% have brain metastases (BrMs) at diagnosis. During the disease course, 25-50% of patients will develop BrMs. Despite available treatments, survival rates for patients with NSCLC and BrMs remain low, and their overall prognosis is poor. Even with newer agents for NSCLC, options for treating BrMs can be limited by their ineffective transport across the blood-brain barrier (BBB) and the unique brain tumor microenvironment. The presence of actionable genomic alterations (AGAs) is a key determinant of optimal treatment selection, which aims to maximize responses and minimize toxicities. The objective of this systematic literature review (SLR) was to understand the current landscape of the clinical management of patients with NSCLC and BrMs, particularly those with AGAs. METHOD: A Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-compliant SLR was conducted to identify studies in patients with BrMs in NSCLC. Searches used the EMBASE and MEDLINE® databases, and articles published between January 1, 2017 and September 26, 2022 were reviewed. RESULTS: Overall, 179 studies were included in the SLR. This subset review focused on 80 studies that included patients with NSCLC, BrMs, and AGAs (19 randomized controlled trials [RCTs], two single-arm studies, and 59 observational studies). Sixty-four of the 80 studies reported on epidermal growth factor receptor (EGFR) mutations, 14 on anaplastic lymphoma kinase (ALK) alterations, and two on both alterations. Ninety-five percent of studies evaluated targeted therapy. All RCTs allowed patients with previously treated, asymptomatic, or neurologically stable BrMs; the percentage of asymptomatic BrMs varied across observational studies. CONCLUSIONS: Although targeted therapies demonstrate systemic benefits for patients with NSCLC, BrMs, and AGAs, there remains a continued need for effective therapies to treat and prevent BrMs in this population. Increased BBB permeability of emerging therapies may improve outcomes for this population.

Local hero: A phase II study of local therapy only (stereotactic radiosurgery and / or surgery) for treatment of up to five brain metastases from HER2+ breast cancer. (TROG study 16.02).

Introduction, A decade ago, stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) was emerging as preferred treatment for oligometastatic brain metastases. Studies of cavity SRS after neurosurgery were underway. Data specific to metastatic HER2 breast cancer (MHBC), describing intracranial, systemic and survival outcomes without WBRT, were lacking. A Phase II study was designed to address this gap. Method, Adults with MHBC, performance status 0-2, ≤ five BrM, receiving/planned to receive HER2-targeted therapy were eligible. Exclusions included leptomeningeal disease and prior WBRT. Neurosurgery allowed ≤6 weeks before registration and required for BrM >4 cm. Primary endpoint was 12-month requirement for WBRT. Secondary endpoints; freedom from (FF-) local failure (LF), distant brain failure (DBF), extracranial disease failure (ECDF), overall survival (OS), cause of death, mini-mental state examination (MMSE), adverse events (AE). Results, Twenty-five patients accrued Decembers 2016-2020. The study closed early after slow accrual. Thirty-seven BrM and four cavities received SRS. Four cavities and five BrM were observed. At 12 months: one patient required WBRT (FF-WBRT 95 %, 95 % CI 72-99), FFLF 91 % (95 % CI 69-98), FFDBF 57 % (95 % CI 34-74), FFECDF 64 % (95 % CI 45-84), OS 96 % (95 % CI 74-99). Two grade 3 AE occurred. MMSE was abnormal for 3/24 patients at baseline and 1/17 at 12 months. Conclusion, At 12 months, SRS and/or neurosurgery provided good control with low toxicity. WBRT was not required in 95 % of cases. This small study supports the practice change from WBRT to local therapies for MHBC BrM.

The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype. SIGNIFICANCE: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

Background: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. Methods: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. Results: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. Conclusions: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.

[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas.

Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.

Dendritic cell vaccine trials in gliomas: Untangling the lines.

Glioblastoma is a deadly brain tumor without any significantly successful treatments to date. Tumor antigen-targeted immunotherapy platforms including peptide and dendritic cell (DC) vaccines, have extended survival in hematologic malignancies. The relatively "cold" tumor immune microenvironment and heterogenous nature of glioblastoma have proven to be major limitations to translational application and efficacy of DC vaccines. Furthermore, many DC vaccine trials in glioblastoma are difficult to interpret due to a lack of contemporaneous controls, absence of any control comparison, or inconsistent patient populations. Here we review glioblastoma immunobiology aspects that are relevant to DC vaccines, review the clinical experience with DC vaccines targeting glioblastoma, discuss challenges in clinical trial design, and summarize conclusions and directions for future research for the development of effective DC vaccines for patients.

Hope in the era of precision oncology: a qualitative study of informal caregivers' experiences.

OBJECTIVES: To explore informal caregivers' perspectives on precision medicine in cancer care. DESIGN: Semi-structured interviews with the informal caregivers of people living with cancer and receiving targeted/immunotherapies. Interview transcripts were analysed thematically using a framework approach. SETTING: Recruitment was facilitated by two hospitals and five Australian cancer community groups. PARTICIPANTS: Informal caregivers (n=28; 16 men, 12 women; aged 18-80) of people living with cancer and receiving targeted/immunotherapies. RESULTS: Thematic analysis identified three findings, centred largely on the pervasive theme of hope in relation to precision therapies including: (1) precision as a key component of caregivers' hope; (2) hope as a collective practice between patients, caregivers, clinicians and others, which entailed work and obligation for caregivers; and (3) hope as linked to expectations of further scientific progress, even if there may be no personal, immediate benefit. CONCLUSIONS: Innovation and change in precision oncology are rapidly reconfiguring the parameters of hope for patients and caregivers, creating new and difficult relational moments and experiences in everyday life and in clinical encounters. In the context of a shifting therapeutic landscape, caregivers' experiences illustrate the need to understand hope as collectively produced, as emotional and moral labour, and as entangled in broader cultural expectations of medical advances. Such understandings may help clinicians as they guide patients and caregivers through the complexities of diagnosis, treatment, emerging evidence and possible futures in the precision era. Developing a better understanding of informal caregivers' experiences of caring for patients receiving precision therapies is important for improving support to patients and their caregivers.

Advances in Treatment of Isocitrate Dehydrogenase (IDH)-Wildtype Glioblastomas.

PURPOSE OF REVIEW: The management of isocitrate dehydrogenase (IDH)-wildtype glioblastomas is an area of unmet need. Despite multimodal therapy incorporating maximal safe resection, radiotherapy, and temozolomide, clinical outcomes remain poor. At disease progression or relapse, available systemic agents such as temozolomide, lomustine, and bevacizumab have limited efficacy. We review the recent advances in the treatment of IDH-wildtype glioblastomas. RECENT FINDINGS: A broad repertoire of systemic agents is in the early stages of development, encompassing the areas of precision medicine, immunotherapy, and repurposed medications. The use of medical devices may present opportunities to bypass the blood-brain barrier. Novel clinical trial designs aim to efficiently test treatment options to advance the field. There are a number of emerging treatment options for IDH-wildtype glioblastomas which are undergoing evaluation in clinical trials. Advances in our scientific understanding of IDH-wildtype glioblastomas offer hope and the prospect of incremental improvements in clinical outcomes.

Characterization of industry relationships in oncology.

BACKGROUND: Collaborative relationships between academic oncology and industry (pharmaceutical, biotechnology, "omic," and medical device companies) are essential for therapeutic development in oncology; however, limited research on engagement in and perceptions of these relationships has been done. METHODS: Survey questions were developed to evaluate relationships between academic oncology and industry. An electronic survey was delivered to 1000 randomly selected members of the American Society of Clinical Oncology, a professional organization for oncologists, eliciting respondents' views around oncology-industry collaborations. The responses were analyzed according to prespecified plans. RESULTS: There were 225 survey respondents. Most were from the United States (70.0%), worked at an academic institution (60.1%), worked in medical oncology (81.2%), and had an active relationship with industry (85.8%). One quarter (26.7%) of respondents reported difficulty establishing a relationship with industry collaborators, and most respondents (75%) did not report having had mentorship in developing these relationships. The majority (85.3%) of respondents considered these collaborations important to their careers. Respondents generally thought that scientific integrity was preserved (92%), and most respondents (95%) had little concern over the quality of the collaborative product. Many (60%) shared concerns over potential conflict of interest if an individual with a compensated relationship promoted an industry product for clinical care/research, yet most respondents (67%) stated these relationships did not shape their interactions with patients. CONCLUSIONS: This study provides novel data characterizing the nature of collaborative relationships between clinicians, researchers, and industry in oncology. Although respondents considered these collaborations an important part of clinical and academic oncology, formal education or mentorship around these relationships was rare. Conflicting findings around conflict of interest highlight the importance of more dedicated research in this area. PLAIN LANGUAGE SUMMARY: Business enterprises in health care play a central role in cancer research and care, driving the development of new medical testing, drugs, and devices. Effective working relationships among clinicians, researchers, and these industry partners can promote innovative research and enhance patient care. Study of these collaborations has been limited to date. Through distribution of a questionnaire to cancer clinicians and researchers, we found that most participants consider these relationships valuable, though they find establishing such relationships challenging partly because of gaps in educational programs in this area. Our findings also highlight the need for further policy around the potential bias these relationships can introduce.

Novel Immunotherapeutic Approaches for the Treatment of Glioblastoma.

Glioblastoma is highly aggressive and remains difficult to treat despite being the most common malignant primary brain tumor in adults. Current standard-of-care treatment calls for maximum resection of the tumor mass followed by concurrent chemotherapy and radiotherapy and further adjuvant chemotherapy if necessary. Despite this regimen, prognosis remains grim. Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include: a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood-brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations. In this review, we present different classes of immunotherapy targeting glioblastoma, their most recent results, and potential future directions.

Durable responses in patients with HER2+ breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan.

Leptomeningeal metastases (LM) are a devastating complication of HER2 + metastatic breast cancer (MBC), with no effective treatments. In a case series of 8 patients with heavily pretreated HER2 + MBC and progressing LM, all 8 patients (100%) derived clinical benefit from Trastuzumab deruxtecan (TDXd), and 4 patients (50%) had an objective partial response based on formal neuroradiology MRI reads using the EORTC/RANO-LM Revised-Scorecard. T-DXd warrants further study in LM in HER2 + MBC and solid tumors where T-DXd may be active.