James Welsh

• MD
• Professor (Associate) at University of Texas MD Anderson Cancer Center

Background: Definitive radiotherapy (dRT) has been shown to be an effective option for patients with oligometastatic and oligoprogressive cancers; however, this approach has not been well-studied in metastatic thyroid cancer. Methods: This retrospective cohort included 119 patients with oligometastatic (34%) and oligoprogressive (66%) metastatic th...

Background BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Here...

Background: Solid tumors remain a significant challenge in cancer therapy due to their resistance to conventional treatments. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising approach for treating solid tumors, but its effectiveness is often limited by the poor infiltration of CAR-T cells into the tumor microenvironment. Th...

Background Low-dose radiation therapy (LD-RT) in combination with immune checkpoint inhibition (ICI) and/or cell therapy has emerged as an effective mediator to restore immune response in solid tumors. However, clinically available biomarkers still fail to effectively predict response and optimize therapy choices. Emerging evidence indicates that n...

Background Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety coh...

Background Proton beam therapy (PBT) has frequently yielded superior results to conventional X-ray therapy. However, combination of PBT with checkpoint inhibitors is rarely reported for treating metastatic cancers. NBTXR3 is a radioenhancer with immunomodulatory capacities able to restore efficacy of anti-PD1 (aPD1) in a model resistant to this tre...

Background Autologous cell therapies with an engineered T-cell receptor targeting MAGE-A4 have shown responses in patients with synovial sarcoma ¹ with additional responses in myxoid/round cell liposarcoma (MRCLS), head and neck, lung, esophagogastric junction, and melanoma cancers. 2 3 Low-dose radiation may control tumor growth locally and modula...

Background TIGIT and LAG3 are inhibitory receptors expressed on cytotoxic CD8+ T cells and NK cells and directly inhibit the activation and proliferation of these cells. We proposed that blockade of TIGIT and LAG3 could improve antitumor immune response in a mouse model of anti-PD1 (aPD1)-resistant mice. Methods 129Sv/Ev mice were inoculated with...

Radiotherapy is known to influence immune function, including T cell receptor (TCR) repertoire. We evaluated the TCR repertoire before and after stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) and explored correlations between TCR indexes and distant failure after SBRT. TCR repertoires were analyzed in periphera...

Background Radiation combined with PD1 blockade offers significant treatment benefits in several tumor types. However, anti-PD1 resistance precludes such benefits in many cases. Here we attempted to overcome anti-PD1 resistance by combining localized radiation with a radioenhancing nanoparticle (NBTXR3) and systemic anti-PD1 treatment to achieve ab...

Introduction: TIGIT and Lag3 are inhibitory receptors expressed on cytotoxic CD8+ T cells and NK cells and directly inhibit the activation and proliferation of these cells. We proposed that blockade of TIGIT and Lag3 could improve antitumor immune response in a mouse model of anti-PD1-resistant mice. Methods: 129Sv/Ev mice were inoculated with 50,0...

Purpose To investigate the incidence and prognosis of severe radiation-induced lymphopenia (sRIL) after postoperative radiotherapy (PORT) for resected NSCLC. Patients and Methods Between 1998 and 2017, 170 patients treated with PORT for NSCLC were retrospectively reviewed. Lymphopenia was divided into tertiles with severe lymphopenia defined as ab...

Background Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge immuno-oncology is facing. Intense efforts are being made to identify combination therapies that could improve ICI response rates. Administered intratumorally, NBTXR3 enhances the energy dos...

Background Although treatment with high-dose (HD) radiation (XRT) and NBTXR3 on primary tumors in combination with systemic anti-PD1 was able to significantly improve abscopal effect in 344SQR murine metastatic lung cancer model, most of the mice eventually died due to the growth of secondary tumors. Therefore, we intended to use HD-XRT plus NBTXR3...

Background In this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC). Methods Patients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included re...

Background Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT...

Background Despite outstanding responses to anti-PD-1 agents in a subset of non-small cell lung cancer (NSCLC) patients, approximately 80% of patients fail to have prolonged favorable response. Recent studies show that tumor cell oxidative metabolism is a barrier to PD-1 immunotherapy and radiotherapy could overcome PD-1 resistance, so it is urgent...

Background Clinical trials are considered the “gold-standard” in evidence-based medicine, yet few cancer patients ultimately enroll. Here we examine patients screened for thoracic radiation oncology (TRO) clinical trials to better understand enrollment trends. Methods A prospective database tracking screening and enrollment for patients referred f...

In Reply We thank Fan and colleagues for their interest in our recent phase 1/2 trial evaluating the use of chemoradiotherapy with a simultaneous integrated boost of radiation in unresectable locally advanced esophageal cancer.¹ First, we are delighted to present more details regarding the cohort of 97 patients used for comparison in our investigat...

Background This study compared response rates and outcomes of combined radiotherapy and immunotherapy (iRT) based on the type of checkpoint inhibitor (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) vs antiprogrammed death-1 (PD1)) for metastatic non-small cell lung cancer (mNSCLC). Methods We retrospectively reviewed two prospective tria...

Background & purpose: We report disease control, survival, and toxicity in patients with advanced inoperable non-small cell lung cancer (NSCLC) receiving concurrent chemotherapy and intensity-modulated proton therapy (IMPT) at a single institution. Material and methods: All patients were treated with IMPT with concurrent chemotherapy. Endpoints...

Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor m...

p>As clinical data are digitized in electronic medical records (EMR), the amount of historical data becomes a challenge for utilization and outcomes studies. An automated approach for structuring clinical data into machine-readable format is essential due to scale. We previously developed MMPower, an ElasticSearch-based technology platform for name...

Purpose: The safety of combined immunotherapy and thoracic radiation therapy (iRT) has been understudied. We evaluated toxicities in patients receiving iRT from 3 single-institutional phase 1/2 trials. Methods and materials: Clinical/treatment characteristics and toxicities (per the Common Toxicity Criteria for Adverse Events, version 4.0) were...

The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitf...

Background: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. Material and methods: Multi-institutional retrospective analysis was con...

Introduction: Extended survival outcomes from improved treatments for patients with cancer come with an increased risk of developing a metachronous second malignancy (MSM). We evaluated the incidence of MSM after successful treatment of SCLC and compared survival between SCLC patients who developed MSM and those who did not. Methods: Selection c...

Importance Proton beam radiotherapy (PBT) has the potential to reduce toxic effects in the definitive management of locally advanced non–small-cell lung cancer (NSCLC), but long-term prospective data are lacking. Objective To report the final (5-year) results of a prospective study evaluating concurrent chemotherapy and high-dose PBT to treat unre...

The mechanisms underlying immunosuppression and resistance to PD1 inhibitors in cancer are not well understood. We attempted to fill this gap with an integrated analysis of mRNA, microRNA, and protein expression in an anti-PD1-resistant lung adenocarcinoma mouse model. The model was created by in vivo passage of 344SQ murine lung cancer cells (p53R...

Introduction: We present serum correlative analysis from a phase II randomized trial to identify markers associated with progression free survival (PFS) in NSCLC. Methods: NSCLC patients presenting with oligometastatic disease (≤3 metastases) were enrolled on a multi-institution phase II randomized trial (NCT01725165). Patients who did not progress...

Purpose: Radiomics has shown great promise to use quantifiable imaging characteristics to predict the behavior and prognosis of neoplasms. This is the first study to evaluate whether radiomic texture analysis can predict outcomes in gastroesophageal junction adenocarcinoma (GEJAC) treated with neoadjuvant chemoradiotherapy (CRT). Materials and Meth...

Purpose Host immunity may affect the outcome of esophageal cancer patients. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for esophageal cancer (EC) and looked for clinically relevant associations with survival. Materials/Methods 504 patients with stage I-III EC (2007–2013)...

Background: The authors evaluated the efficacy, patterns of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for patients with medically inoperable, clinical stage I non-small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years of follow-up. Clinical staging was performed according to the seventh edition of the...

Several factors must be considered to successfully integrate immunotherapy with radiation into clinical practice. One such factor is that concepts arising from preclinical work must be tested in combination with radiation in preclinical models to better understand how combination therapy will work in patients; examples include checkpoint inhibitors...

Objectives: Our goal was to evaluate stereotactic ablative radiotherapy (SABR) as a salvage option for isolated recurrence of non-small-cell lung cancer (NSCLC) in the lung parenchyma following definitive treatment of stage I-III disease. Methods: Patients who had histologically confirmed, positron emission tomography (PET) staged, isolated NSCL...

Purpose: Accelerated hypofractionated radiation therapy (AHRT) is increasingly used for select lung cancer patients. We evaluated clinical outcomes and predictors of pulmonary/esophageal toxicity in patients treated with ≥52.5 Gy in 15 fractions. Methods and materials: We evaluated 229 patients treated with radiation therapy doses ≥52.5 Gy in 15...

We thank Hiniker and colleagues for their interest in our work ([1][1]). We are delighted to hear that their patient continues to maintain a prolonged disease-free interval for now >5 years ([2][2]). We have also read with great interest their recent article reporting on the combination of

Purpose: To discern the effectiveness and toxicity of stereotactic ablative radiation therapy (SABR) in the elderly population (aged ≥75 years) and to consider how SABR outcomes compare with surgical outcomes historically reported in the elderly. Methods and materials: A total of 772 patients with clinical early-stage I-II non-small cell lung ca...

Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-defici...

Background: There are few data to support the use of varying imaging modalities in evaluating recurrence in non-small-cell lung cancer (NSCLC). We compared the efficacy of surveillance positron emission tomography (PET)/computed tomography (CT) versus CT scans of the chest in detecting recurrences after definitive radiation for NSCLC. Materials a...

Purpose: Challenges can arise when attempting to maximize patient enrollment in clinical trials. There have been limited studies focusing on the barriers to enrollment and the efficacy of alternative study design to improve accrual. We analyzed barriers to clinical trial enrollment, particularly the influence of timing, in context of three prospec...

Introduction: Approximately 50% of recurrences after standard-dose chemoradiation for locally advanced esophageal cancer occur within the gross tumor volume (GTV). In this prospective phase I/II clinical trial, we explored use of a simultaneous integrated boost (SIB) dose to the GTV. Methods: Forty-four patients with unresectable esophageal canc...

Purpose: Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab. Experimental design: SABR was given either concurrently (1 day after the first dose) or sequentia...

Purpose: We report our single-institution experience with stereotactic ablative radiotherapy (SABR) for adrenal metastasis and identify factors influencing outcomes, patterns of failure, and dosimetric thresholds for toxicity. Methods and materials: We identified patients with adrenal metastases treated with SABR from 2009 to 2015. Toxicity was...

Immunotherapies targeting programmed cell death receptor-1 (PD-1) have shown some clinical success, validating the role of immune modulation in the treatment of cancer. However, only 18% of non-small cell lung cancer patients have responded to anti-PD1 treatment thus far, the remaining 82% have not. This raises fundamental questions about mechanism...

Immunotherapy, particularly immune-checkpoint inhibition, is producing encouraging clinical responses and affecting the way numerous cancers are treated. Yet immune-checkpoint therapy is not effective for many patients, and even those who initially respond can experience relapse, fueling interest in finding new processes or tools to improve the eff...

MolecularMatch was created as a way for physicians and patients to make sense of genomics and other diagnostic data as it relates to therapeutics and clinical trials. This workshop will explore the journey patients and their families face as they are diagnosed with cancer and weighing their options. Concurrently physicians are also challenged with...

Purpose: Fifteen fraction treatment schedules are increasingly used to deliver high doses of radiation therapy (RT) to both lung and hepatobiliary malignancies. The purpose of our study was to examine the incidence and predictors of chest wall (CW) toxicity in patients treated with this regimen. Methods and materials: We evaluated 135 patients t...

The use of radiation for cancer therapy has expanded and sparked interest in possible synergistic effects by combining it with current immunotherapies. In this review, we present a case of a patient who responded to programmed cell death 1 (PD1) blockade and radiation therapy and discuss possible mechanisms. We provide background on the blockade of...

Understanding of the biological underpinnings of the development of metastatic disease and therapeutic resistance has greatly increased over the past few decades. Initially, these insights came slowly because only one protein or gene or signaling pathway could be studied at a time. The process of elucidating how one gene could influence downstream...

Purpose: To identify the optimal dose parameters predictive for local/lobar control after stereotactic ablative radiation therapy (SABR) in early-stage non-small cell lung cancer (NSCLC). Methods and materials: This study encompassed a total of 1092 patients (1200 lesions) with NSCLC of clinical stage T1-T2 N0M0 who were treated with SABR of 50...

An overview of MolecularMatch technology was presented detailing code base infrastructure as applied to clinical genomics application in oncology.

MiR-34a, an important tumor-suppressing microRNA, is downregulated in several types of cancer; loss of its expression has been linked with unfavorable clinical outcomes in non-small-cell lung cancer (NSCLC), among others. MiR-34a represses several key oncogenic proteins, and a synthetic mimic of miR-34a is currently being tested in a cancer trial....

Endogenous levels of miR-34a in non-small cell lung cancer lines (NSCLC).

List of the 58 DNA damage and repair genes analyzed using a custom 384-well PCR array.

Primers designed for gene expression analysis by quantitative polymerase chain reaction.

Correlation of miR-34a expression and DNA damage and repair genes in 532 patients with NSCLC from The Cancer Genome Atlas data set.

Background: Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), the regulation of PDL1 expression is poorly understood. Here, we show that PDL1 is regulated by p53 via miR-34. Methods: p53 wild-type and p53-deficient cell lines (p53(-/-) and p53(+/+) HCT116, p53-inducible H1299, an...

Immunotherapy has become one of the most profound advances in the treatment of solid tumors. Unlike the prior targeted therapies such as kinase inhibitors, there are no clear mutations or definitive biomarkers of which patients are likely to respond. It is well documented that many patients with PDL1 negative tumors can still have profound response...

Background: The immune system has important roles in tumor development and outcomes after cancer treatment. We evaluated whether single-nucleotide polymorphisms (SNPs) in the gene encoding casitas B-lineage lymphoma b protein (Cbl-b), an E3 ubiquitin ligase that maintains immune tolerance by negatively regulating T-cell activation and function, we...

The expression of the cell membrane receptor and proto-oncogene c-Met has been linked with numerous aspects of cancer development, among the best characterized of which are the development of metastasis and the development of resistance toward molecularly targeted therapeutics. This chapter covers aspects of c-Met expression in various types of tum...

Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechani...

Background Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), little is known of how PDL1 expression is regulated. We previously found that miR-200s directly regulate PDL1; here we show that PDL1 is regulated by miR-34a and p53. Methods We confirmed that PDL1 is a direct target of mi...