Benjamin T. Cooper

Combinations of Immunotherapy and Radiation in Cancer Therapy

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.

Weekly versus every-three-weeks platinum-based chemoradiation regimens for head and neck cancer.

BackgroundThe majority of chemoradiation (CRT) trials for locally advanced head and neck squamous cell carcinoma (HNSCC) have relied on platinum-based chemotherapy regimens administered every-3-weeks. However, given the increased utilization of weekly platinum regimens, it remains unclear how different chemotherapy schedules compare regarding efficacy and toxicity.MethodsWe retrospectively identified 212 patients with HNSCC who were treated at a single academic medical center with concurrent platinum-based CRT given weekly (N = 68) or every-three-weeks (N = 144). JMP version 10 (SAS Institute) was used for statistical analysis. Discrete variables were compared with the chi-square test and differences in the medians were assessed using the Wilcoxon test. Survival curves were constructed using the Kaplan-Meier method and significance was assessed using the log rank test. For univariate analysis and multivariate analysis, we used Cox proportional hazard or logistic regression models to compare differences in survival or differences in categorical variables, respectively.ResultsPatients receiving weekly platinum regimens were more likely to be older (median age 61.4 vs. 55.5 y; P < .001), have high or very high Charlson comorbidity index (45.6% vs. 27.8%; P = .01), and receive carboplatin-based chemotherapy (6.3% vs. 76.5%; P < .001). Weekly and every-3-week platinum regimens had similar locoregional control (HR 1.10; 95% CI 0.63–1.88; P = .72), progression-free survival (HR 1.13; 95% CI 0.75–1.69; P = .55), and overall survival (HR 1.11; 95% CI 0.64–1.86; P = .71). Every-3-weeks platinum regimens were associated with increased days of hospitalization (median: 3 days vs. 0 days; P = .03) and acute kidney injury (AKI) during radiotherapy (50.0% vs. 22.1%; P < .001). On multivariate analysis, AKI was significantly associated with every-3-weeks regimens (OR: 24.38; 95% CI 3.00–198.03; P = .003) and high comorbidity scores (OR: 2.74; 95% CI 2.15–5.99; P = .01).ConclusionsOur results suggest that every-3-weeks and weekly platinum-containing CRT regimens have similar disease control but weekly platinum regimens are associated with less acute toxicity.

Preplanning prediction of the left anterior descending artery maximum dose based on patient, dosimetric, and treatment planning parameters

Purpose Maximum dose to the left anterior descending artery (LADmax) is an important physical constraint to reduce the risk of cardiovascular toxicity. We generated a simple algorithm to guide the positioning of the tangent fields to reliably maintain LADmax <10 Gy. Methods and materials Dosimetric plans from 146 consecutive women treated prone to the left breast enrolled in prospective protocols of accelerated whole breast radiation therapy, with a concomitant daily boost to the tumor bed (40.5 Gy/15 fraction to the whole breast and 48 Gy to the tumor bed), provided the training set for algorithm development. Scatter plots and correlation coefficients were used to describe the bivariate relationships between LADmax and several parameters: distance from the tumor cavity to the tangent field edge, cavity size, breast separation, field size, and distance from the tangent field. A logistic sigmoid curve was used to model the relationship of LADmax and the distance from the tangent field. Furthermore, we tested this prediction model on a validation data set of 53 consecutive similar patients. Results A lack of linear relationships between LADmax and distance from cavity to LAD (−0.47), cavity size (−0.18), breast separation (−0.02), or field size (−0.28) was observed. In contrast, distance from the tangent field was highly negatively correlated to LADmax (-0.84) and was used in the models to predict LADmax. From a logistic sigmoid model we selected a cut-point of 2.46 mm (95% confidence interval, 2.19-2.74 mm) greater than which LADmax is <10 Gy (95% confidence interval, 9.30-10.72 Gy) and LADmean is <3.3 Gy. Conclusions Placing the edge of the tangents at least 2.5 mm from the closest point of the contoured LAD is likely to assure LADmax is <10 Gy and LADmean is <3.3 Gy in patients treated with prone accelerated breast radiation therapy.

Radiotherapy induces responses of lung cancer to CTLA-4 blockade

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1–3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4–6. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.Radiotherapy-induced abscopal responses enhance the efficacy of anti-CTLA-4 in patients with non-small-cell lung cancer.

Dosimetric assessment of tumor control probability in intensity and volumetric modulated radiotherapy plans

OBJECTIVE: Radiobiological models have been used to calculate the outcomes of treatment plans based on dose-volume relationship. This study examines several radiobiological models for the calculation of tumor control probability (TCP) of intensity modulated radiotherapy plans for the treatment of lung, prostate, and head and neck (H&N) cancers. METHODS: Dose volume histogram (DVH) data from the intensity modulated radiotherapy plans of 36 lung, 26 prostate, and 87  H&N cases were evaluated. The Poisson, Niemierko, and Marsden models were used to calculate the TCP of each disease group treatment plan. The calculated results were analyzed for correlation and discrepancy among the three models, as well as different treatment sites under study. RESULTS: The median value of calculated TCP in lung plans was 61.9% (34.1-76.5%), 59.5% (33.5-73.9%) and 32.5% (0.0-93.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in prostate plans was 85.1% (56.4-90.9%), 81.2% (56.1-88.7%) and 62.5% (28.2-75.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in H&N plans was 94.0% (44.0-97.8%) and 94.3% (0.0-97.8%) with the Poisson and Niemierko models, respectively. There were significant differences between the calculated TCPs with the Marsden model in comparison with either the Poisson or Niemierko model (p < 0.001) for both lung and prostate plans. The TCPs calculated by the Poisson and Niemierko models were significantly correlated for all three tumor sites. CONCLUSION: There are variations with different radiobiological models. Understanding of the correlation and limitation of a TCP model with dosimetric parameters can help develop the meaningful objective functions for plan optimization, which would lead to the implementation of outcome-based planning. More clinical data are needed to refine and consolidate the model for accuracy and robustness. ADVANCES IN KNOWLEDGE: This study has tested three radiobiological models with varied disease sites. It is significant to compare different models with the same data set for better understanding of their clinical applicability.

A DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas.

Purpose Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wide DNA methylation based classifier to differentiate between osteosarcoma, Ewings sarcoma, and synovial sarcoma. Materials and Methods DNA methylation status of 482,421 CpG sites in 10 Ewings sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas (TCGA) synovial sarcoma, TARGET Osteosarcoma, and a recently published series of Ewings sarcoma. Results Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were accurately classified as synovial sarcoma (10/10, sensitivity and specificity 100%), all but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and 14/15 Ewings sarcoma samples classified correctly (sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA-seq although no fusion was found on manual curation of the transcript sequence. Two additional clinical samples, that were difficult to classify by morphology and molecular methods, were classified as osteosarcoma when previously suspected to be a synovial sarcoma and Ewings sarcoma on initial diagnosis, respectively. Conclusion Osteosarcoma, synovial sarcoma, and Ewings sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histological and standard techniques are inconclusive.

The Immune System and Its Contribution to the Radiotherapeutic Response of Glioblastoma

The immune system plays an important role in both counteracting and facilitating cancer development, as well as contributing to the effects of standard cancer treatments. As such, the immune system is most certainly involved in the response of glioblastoma to radiotherapy; however, it is difficult to elucidate the specific role of immunity due to limitations in animal models and the difficulty in obtaining tissue to study molecular correlates of progression and response. Yet there is abundant evidence that leukocytes and other immune mediators recognize and respond to glioma cells, and indirect evidence that they participate in the therapeutic response to radiation. After a brief introduction on the role of the innate and adaptive immune response to cancer, we review the effects of radiotherapy on the anti-tumor immune response, including inflammation, T-cell priming, and immune suppression. We first introduce the concept of radiation induced immunogenic cell death, its application to the unique immunological landscape of the CNS, and present available evidence that radiation induces an immune response against glioblastoma. We then discuss some of the barriers of the brain/tumor microenvironment that may interfere with effective anti-tumor immunity, and conclude with suggested approaches to better harness the immune response in the treatment of glioblastoma with radiotherapy.

Use of a Flexible Inflatable Multi-Channel Applicator for Vaginal Brachytherapy in the Management of Gynecologic Cancer.

Introduction Evaluate use of novel multi-channel applicator (MC) Capri™ to improve vaginal disease coverage achievable by single-channel applicator (SC) and comparable to Syed plan simulation. Materials and methods Twenty-eight plans were evaluated from four patients with primary or recurrent gynecologic cancer in the vagina. Each received whole pelvis radiation, followed by three weekly treatments using HDR brachytherapy with a 13-channel MC. Upper vagina was treated to 5 mm depth to 1500 cGy/3 fractions with a simultaneous integrated boost totaling 2100 cGy/3 fractions to tumor. Modeling of SC and Syed plans was performed using MC scans for each patient. Dosimetry for MC and SC plans was evaluated for PTV700 cGy coverage, maximum dose to 2 cm3 to bladder, rectum, as well as mucosal surface points. Dosimetry for Syed plans was calculated for PTV700 cGy coverage. Patients were followed for treatment response and toxicity. Results Dosimetric analysis between MC and SC plans demonstrated increased tumor coverage (PTV700 cGy), with decreased rectal, bladder, and contralateral vaginal mucosa dose in favor of MC. These differences were significant (p < 0.05). Comparison of MC and Syed plans demonstrated increased tumor coverage in favor of Syed plans which were not significant (p = 0.71). Patients treated with MC had no cancer recurrence or ≥grade 3 toxicity. Conclusion Use of MC was efficacious and safe, providing superior coverage of tumor volumes ≤1 cm depth compared to SC and comparable to Syed implant. MC avoids excess dose to surrounding organs compared to SC, and potentially less morbidity than Syed implants. For tumors extending ≤1 cm depth, use of MC represents an alternative to an interstitial implant.

Toxicity and disease-related outcomes after radiotherapy for head and neck cancer in human immunodeficiency virus-positive patients

Background: Human immunodeficiency virus (HIV) seropositivity may be associated with higher risk of local recurrence and poor survival in multiple malignancies. However, long-term disease control in HIV-positive patients with head and neck cancer (HNC) is not well described. The purpose of this study is to review the disease-related outcomes of HIV-positive patients who underwent radiotherapy (RT) or chemoradiotherapy (CRT) at our institution. Methods: We retrospectively reviewed 24 HIV-positive patients who underwent RT for HNC between 2004 and 2013. Patient characteristics, treatment details, and outcomes were collected. Overall survival (OS) and local recurrence-free survival (LRFS) were investigated. Kaplan–Meier estimated survival was calculated. Results: Median follow-up was 21 months. All patients were treated with curative intent. Eighty-three percent had stage III–IV. Primary sites of disease included oropharynx (n = 12), larynx (n = 6), oral cavity (n = 2), unknown primary (n = 2), nasal cavity (n = 1), and paranasal sinuses (n = 1). Four patients (17%) had definitive RT alone and nine had definitive CRT (38%; eight cisplatin and one cetuximab). Eleven (46%) were treated in the adjuvant setting after surgical resection; six with RT alone and five with concurrent cisplatin. Eight patients had acute Grade 3 toxicity with no acute Grade 4 or 5 toxicities. Fifteen patients (63%) were alive and disease-free. Two- and 5-year OS was 67 and 59%, respectively. LRFS at 2-years was 82%. Median OS was 83 months. Conclusion: In this cohort, HIV-positive patients treated aggressively with curative intent had excellent OS and local control following RT or CRT for HNC compared to historical controls. Treatment was relatively well tolerated. This group of patients should be managed aggressively with intent to cure.