Hari Menon, MD

Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control.

PMID:35008385 | PMC:PMC8750272 | DOI:10.3390/cancers14010221

Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b+ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4+ and CD8+ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease.

PMID:33340886 | PMC:PMC7750418 | DOI:10.1016/j.tranon.2020.100983

Aim: To explore management trends in preinvasive and cT1-T3 penile cancer. Materials & methods: The National Cancer Database was queried (2004-2013) for cT1-T3 M0 penile cancer with specified nonpalliative surgical techniques and histologies (n = 5,728). Results: Local excision (39%) and partial penectomy (38%) were most commonly utilized. Patients with cTis/Ta or cT1 disease more often received nonpenectomy approaches (p < 0.05); cT2-T3 cases more likely underwent penectomy (p < 0.001). No survival differences were observed between penectomy (49.3 months) and nonpenectomy approaches (50.3 months) in the overall cohort (p = 0.107) and when stratifying by T-stage (p > 0.20 for all). Conclusion: This study provides contemporary insight into the landscape for management of this rare disease and can serve as a benchmark for future evaluation of treatment trends.

PMID:32301342 | DOI:10.2217/fon-2020-0067

PURPOSE: This review explores the use of intensity modulated radiation therapy (IMRT) after lung-sparing surgery in malignant pleural mesothelioma (MPM). Because severe toxicities have been documented after radiation therapy for MPM, its use remains controversial, especially as modern surgical management has shifted toward lung-sparing pleurectomy/decortication. IMRT is an advanced technique that may allow for safer radiation therapy delivery, but there remains limited data (including no summative data) to support this notion.

METHODS AND MATERIALS: We performed a systematic review evaluating the safety and efficacy of post-pleurectomy IMRT (P-IMRT). A systematic review of PubMed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted for publications of all dates that specifically reported clinical outcomes and/or toxicities of P-IMRT in patients with MPM. Ten original studies were included in this review.

RESULTS: The incidence of grade 3 pneumonitis ranged from 0% to 16%, with all but 2 studies reporting rates below 9%. Grade 4 and 5 pneumonitis were observed in less than 1.5% of cases, except in one publication that used hypofractionated radiation therapy to doses >60 Gy. Crude local failure rates ranged from 19% to 60%, median progression free survival ranged from 12 to 16 months, and median overall survival ranged from 19 to 28 months.

CONCLUSIONS: P-IMRT produces relatively few higher-grade toxicities and has reasonable disease-related outcomes, especially when delivered using conventionally fractionated regimens to doses of 45 to 54 Gy and exercising careful attention to dose constraints during treatment planning. IMRT can thus be considered in well-selected patients in whom adequate survival after pleurectomy is expected. These data also support the initiation of the phase III NRG-LU006 trial of extended pleurectomy/decortication and chemotherapy with or without IMRT.

PMID:32088429 | DOI:10.1016/j.prro.2020.02.007

Aims: To analyze outcomes in primary anorectal melanoma, a rare disease with limited data and treatment guidelines. Materials & methods: We analyzed 305 subjects in the National Cancer Database from 2004 to 2015. The primary end point was overall survival (OS). Results: Surgery was predictive of OS (median 2.24 vs 1.18 years; p = 0.009) with no survival difference between local and transabdominal approaches (p = 0.77). No OS benefit was seen with chemotherapy (p = 0.16), radiotherapy (p = 0.31) or adjuvant therapy post surgery (p > 0.05 for all groups). Targeted therapy trended toward higher survival in metastatic patients (1.33 vs 0.55 years; p = 0.06). Conclusion: In nonmetastatic patients, surgery of any method is associated with a survival benefit. The trend for improved survival following targeted therapy in metastatic patients merits further exploration.

PMID:32067486 | DOI:10.2217/fon-2019-0715

Positron emission tomography (PET) is an advanced functional imaging modality in oncology care for the diagnosis, staging, prognostication, and surveillance of numerous malignancies. PET can also offer considerable advantages for target volume delineation as part of radiation treatment planning. In this review, data and clinical practice from 6 general oncology disease sites are assessed to descriptively evaluate the role of PET in target volume delineation. Also highlighted are several specific and practical utilities for PET imaging in radiation treatment planning. Publication of several ongoing prospective trials in the future may further expand the utility of PET for target delineation and patient care.

PMID:31735301 | DOI:10.1016/j.cpet.2019.08.002

The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma data set showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1β was positively associated with GILT expression in melanoma specimens. These cytokines were capable of inducing GILT expression in human melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT's association with patient outcome, we investigated pathways related to GILT function and expression. In contrast to healthy skin specimens, in which the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway in the The Cancer Genome Atlas melanoma specimens. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II Ag presentation pathway in melanoma outcome.

PMID:31591149 | PMC:PMC6832889 | DOI:10.4049/jimmunol.1900476

PURPOSE: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy.

EXPERIMENTAL DESIGN: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response.

RESULTS: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8+ and NK cells populations measured by granzyme B expression with upregulation of CD8+CD103+ tissue-resident memory cells (TRM) within the abscopal tumor microenvironment relative to radiation only.

CONCLUSIONS: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of TRM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.

PMID:31540976 | PMC:PMC6911635 | DOI:10.1158/1078-0432.CCR-19-0795

Plaque brachytherapy is a well-accepted modality to manage selected cases of ocular melanoma. Although this modality provides validated oncologic and quality of life benefits, severe complications and adverse events can occur. This article reviews complications and adverse events of plaque brachytherapy, including scleral necrosis, strabismus, cataract, glaucoma, and retinopathies as well as management of these conditions. For practicing oncologists and ophthalmologists, these complications are important to understand, identify, and treat. Additionally, an understanding of common complications of brachytherapy should influence the decision of pursuing it as a treatment option.

PMID:31523242 | PMC:PMC6737573 | DOI:10.5114/jcb.2019.87407

BACKGROUND: Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting.

METHODS: A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1-20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types.

RESULTS: The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1-19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.0001). The median change for longest diameter size for low-dose lesions was - 38.5% compared to 8% in no-dose lesions (P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (P = 0.0004).

CONCLUSIONS: Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.

PMID:31484556 | PMC:PMC6727581 | DOI:10.1186/s40425-019-0718-6

OBJECTIVE: Women with cervical cancer (CC) found to have positive surgical margins, positive lymph nodes, and/or parametrial invasion receive a survival benefit from postoperative chemoradiotherapy (CRT) vs. radiation therapy (RT) alone. However, older women may not benefit to the same extent, as they are at increased risk of death from non-oncologic causes as well as toxicities from oncologic treatments. This study sought to evaluate whether there was a survival benefit of CRT over RT in elderly patients with cervical cancer.

METHODS: The National Cancer Database was queried for patients ≥70 years old with newly diagnosed IA2, IB, or IIA CC and positive margins, parametrial invasion, and/or positive nodes on surgical resection. Statistics included logistic regression, Kaplan-Meier overall survival (OS), and Cox proportional hazards modeling analyses.

RESULTS: Altogether, 166 patients met inclusion criteria; 62 (37%) underwent postoperative RT and 104 (63%) underwent postoperative CRT. Younger patients and those living in areas of higher income were less likely to receive CRT, while parametrial invasion and nodal involvement were associated with an increased likelihood (p<0.05 for all). There were no OS differences by treatment type. Subgroup analysis by number of risk factors, as well as each of the 3 risk factors separately, also did not reveal any OS differences between cohorts.

CONCLUSION: In the largest such study to date, older women with postoperative risk factor(s) receiving RT alone experienced similar survival as those undergoing CRT. Although causation is not implied, careful patient selection is paramount to balance treatment-related toxicity risks with theoretical outcome benefits.

PMID:30207105 | PMC:PMC6189436 | DOI:10.3802/jgo.2018.29.e97