More than 60 years ago, the effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the abscopal effect ...(from 'ab scopus', that is, away from the target). The abscopal effect has been connected to mechanisms involving the immune system. However, the effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the abscopal effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.
Phase 3 clinical trial trends demonstrate a widening gap between the rates of systemic and local therapy trials, with the former increasing whereas the latter stagnates. This editorial provides an ...overview of the key points found by Sherry and colleagues in their analysis of >700 trials and allows for actionable interventions in the design of future trials to optimize clinical outcomes and dissemination into practice.
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment over the past decade. However, although the immune landscape suggests a strong rationale for the use of these agents in ...patients with head and neck squamous cell carcinoma, the available clinical evidence indicates that most patients currently do not respond to ICI monotherapy. Radiotherapy is a primary treatment modality for many patients with locally advanced head and neck cancer. While ionizing radiation traditionally has been thought to act in a purely cytotoxic fashion, a growing body of preclinical studies have demonstrated additional profound immunomodulatory effects. Consequently, there has been a surge of interest in the potential synergy between radiotherapy and immunotherapy, both the potential for radiotherapy to augment the systemic anti-tumor immune response and the potential for immunotherapy to improve in-field tumor response to radiation. In this review, we summarize the current preclinical and clinical evidence for radioimmunotherapy, with a particular focus on studies directly relevant to head and neck squamous cell carcinoma, as well as existing challenges and future directions for this emerging field.
Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown ...whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival.
We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models.
One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161 cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P = .002) and after courses >5 fractions (P = .003). Extracranial and >5-fraction RT was associated with increased odds of severe lymphopenia (ALC <500) at the end of RT (odds ratio OR, 3.7; P = .001; and OR, 3.9; P = .001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P = .0001), particularly when RT was administered in the previous 3 months (OR, 189; P < .0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P = .03).
Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.
Head and neck cancers are a diverse group of malignancies that includes an increasing number of virally mediated cancers in addition to tumors caused by tobacco and alcohol use. In both cases, tumor ...development is intimately related to the host immune system, and the status of an endogenous antitumor response is likely prognostic. Virally mediated cancers provide unique targets for preventive vaccines that generate immune responses directed against virus-associated antigens. Once head and neck tumors develop, they are commonly treated with surgery, radiotherapy, and/or chemotherapy. These treatments are associated with significant toxicities, and despite this, subgroups of patients respond poorly and are likely to relapse and die of their disease. Tumor immunotherapy may allow for improvements in both treatment-associated toxicity and outcome. In addition to providing specific targets for therapeutic vaccines and adoptive therapy, virally associated cancers may also be particularly dependent on immune checkpoints; therefore, immune checkpoint inhibitors are being actively tested for these diseases. Cancers that are not virally mediated may also respond to immunotherapies, and biomarkers that could predict response to immunotherapy irrespective of viral status are being evaluated. Multiple ongoing studies are testing benefits of immunotherapy in the management of metastatic squamous cell carcinoma of the head and neck. Early promising results pave the way for future studies that will expand testing to nonmetastatic diseases and other types of head and neck cancers. Prospects of combining various immunotherapies and more established treatments such as chemotherapy and radiotherapy are very intriguing and may provide synergistic benefits.
The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory ...malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti-programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors.
Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of
or
MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR).
Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade.
A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.
Nutritional epidemiology is a highly prolific field. Debates on associations of nutrients with disease risk are common in the literature and attract attention in public media.
We aimed to examine the ...conclusions, statistical significance, and reproducibility in the literature on associations between specific foods and cancer risk.
We selected 50 common ingredients from random recipes in a cookbook. PubMed queries identified recent studies that evaluated the relation of each ingredient to cancer risk. Information regarding author conclusions and relevant effect estimates were extracted. When >10 articles were found, we focused on the 10 most recent articles.
Forty ingredients (80%) had articles reporting on their cancer risk. Of 264 single-study assessments, 191 (72%) concluded that the tested food was associated with an increased (n = 103) or a decreased (n = 88) risk; 75% of the risk estimates had weak (0.05 > P ≥ 0.001) or no statistical (P > 0.05) significance. Statistically significant results were more likely than nonsignificant findings to be published in the study abstract than in only the full text (P < 0.0001). Meta-analyses (n = 36) presented more conservative results; only 13 (26%) reported an increased (n = 4) or a decreased (n = 9) risk (6 had more than weak statistical support). The median RRs (IQRs) for studies that concluded an increased or a decreased risk were 2.20 (1.60, 3.44) and 0.52 (0.39, 0.66), respectively. The RRs from the meta-analyses were on average null (median: 0.96; IQR: 0.85, 1.10).
Associations with cancer risk or benefits have been claimed for most food ingredients. Many single studies highlight implausibly large effects, even though evidence is weak. Effect sizes shrink in meta-analyses.
Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated ...with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.
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•Neoadjuvant ICB induces local and systemic T cell responses in oral cancer patients•Treatment-responsive T cell clones recognize self-antigens including tumor antigens•Responding T cells in tumors display a tissue-resident memory program•Circulating PD-1+KLRG1-CD8 T cell frequency correlates with pathological response
Analysis of immune cell kinetics in oral cancer patients responding to neoadjuvant immune checkpoint blockade identifies diverse features in circulating and tumor-infiltrating T cell subpopulations that underlie rapid response to therapy and correlate with pathological outcome.
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