Although novel therapies, including immunotherapy, have dramatically improved outcomes for many patients with cancer, overall outcomes are heterogeneous and existing biomarkers do not reliably ...predict response. To date, predictors of response to cancer therapy have largely focused on tumour-intrinsic features; however, there is growing evidence that other host factors (eg, host genomics and the microbiome) can substantially affect therapeutic response. The microbiome, which refers to microbiota within a host and their collective genomes, is becoming increasingly recognised for its influence on host immunity, as well as therapeutic responses to cancer treatment. Importantly, microbiota can be modified via several different strategies, affording new angles in cancer treatment to improve outcomes. In this Review, we examine the evidence on the role of the microbiome in cancer and therapeutic response, factors that influence and shape host microbiota, strategies to modulate the microbiome, and present key unanswered questions to be addressed in ongoing and future research.
Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma
. We investigated this regimen in ...patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate
. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial
, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.
Historically, cancer research and therapy have focused on malignant cells and their tumor microenvironment. However, the vascular, lymphatic and nervous systems establish long-range communication ...between the tumor and the host. This communication is mediated by metabolites generated by the host or the gut microbiota, as well by systemic neuroendocrine, pro-inflammatory and immune circuitries-all of which dictate the trajectory of malignant disease through molecularly defined biological mechanisms. Moreover, aging, co-morbidities and co-medications have a major impact on the development, progression and therapeutic response of patients with cancer. In this Perspective, we advocate for a whole-body 'ecological' exploration of malignant disease. We surmise that accumulating knowledge on the intricate relationship between the host and the tumor will shape rational strategies for systemic, bodywide interventions that will eventually improve tumor control, as well as quality of life, in patients with cancer.
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal ...microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.
Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to ...examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.
This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study.
The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib n=599 and vemurafenib plus cobimetinib n=240), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine n=207 and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab n=331), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine n=320 and n=221) were classified according to BMI as normal (694 36% patients), overweight (711 37%), or obese (513 27%). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio HR 0·77 95% CI 0·66–0·90 for progression-free survival and 0·74 0·58–0·95 for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 0·57–0·91 for progression-free survival and 0·60 0·45–0·79 for overall survival) and immunotherapy (HR 0·75 0·56–1·00 and 0·64 0·47–0·86). No associations were observed with chemotherapy (HR 0·87 0·65–1·17, pinteraction=0·61 for progression-free survival and 1·03 0·80–1·34, pinteraction=0·01 for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 0·40–0·70), but no associations observed in women (HR 0·85 0·61–1·18, pinteraction=0·03).
Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations.
ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.
T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly ...understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors.
This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy.
Purpose of Review
We discuss how potentially modifiable factors including obesity, the microbiome, diet, and exercise may impact melanoma development, progression, and therapeutic response.
Recent ...Findings
Obesity is unexpectedly associated with improved outcomes with immune and targeted therapy in melanoma, with early mechanistic data suggesting leptin as one mediator. The gut microbiome is both a biomarker of response to immunotherapy and a potential target. As diet is a major determinant of the gut microbiome, ongoing studies are examining the interaction between diet, the gut microbiome, and immunity. Data are emerging for a potential role of exercise in reducing hypoxia and enhancing anti-tumor immunity, though this has not yet been well-studied in the context of contemporary therapies.
Summary
Recent data suggests energy balance may play a role in the outcomes of metastatic melanoma. Further studies are needed to demonstrate mechanism and causality as well as the feasibility of targeting these factors.
Cancer in adolescents and young adults (AYAs) (15-39 years) is increasingly recognized as a distinct clinical and biological entity. Cancer of unknown primary (CUP), a disease traditionally ...presenting in older adults with a median age of 65 years, poses several challenges when diagnosed in AYA patients. This study describes clinicopathological features, outcomes and challenges in caring for AYA-CUP patients.
A retrospective review of 47 AYAs diagnosed with CUP at MD Anderson Cancer Center (6/2006-6/2013) was performed. Patients with favorable CUP subsets treated as per site-specific recommendations were excluded. Demographics, imaging, pathology and treatment data was collected using a prospectively maintained CUP database. Kaplan-Meier product limit method and log-rank test were used to estimate and compare overall survival. The cox-proportional model was used for multivariate analyses.
Median age was 35 years (range 19-39). All patients underwent comprehensive workup. Adenocarcinoma was the predominant histology (70%). A median of 9 immunostains (range 2-29) were performed. The most common putative primary was biliary tract based on clinicopathological parameters as well as gene profiling. Patients presented with a median of 2 metastatic sites lymph node (60%), lung (47%), liver (38%) and bone (34%). Most commonly used systemic chemotherapies included gemcitabine, fluorouracil, taxanes and platinum agents. Median overall survival for the entire cohort was 10.0 (95% confidence interval (CI): 6.7-15.4) months. On multivariate analyses, elevated lactate dehydrogenase (Hazard ratio (HR) 3.66; 95%CI 1.52-8.82; P = 0.004), ≥3 metastatic sites (HR 5.34; 95%CI 1.19-23.9; P = 0.029), and tissue of origin not tested (HR 3.4; 95%CI 1.44-8.06; P = 0.005) were associated with poor overall survival. Culine's CUP prognostic model (lactate dehydrogenase, performance status, liver metastases) was validated in this cohort (median overall survival: good-risk 25.2 months vs. poor-risk 6.1 months).
AYA-CUP is associated with a poor prognosis. In the current "-omics" era collaborative research efforts towards understanding tumor biology and therapeutic targets in AYA-CUP is an unmet need, necessary for improving outcomes in young CUP patients.
The gut microbiome (GMB) plays a substantial role in human health and disease. From affecting gut barrier integrity to promoting immune cell differentiation, the GMB is capable of shaping host ...immunity and thus oncogenesis and anti-cancer therapeutic response, particularly with immunotherapy. Dietary patterns and components are key determinants of GMB composition, supporting the investigation of the diet-microbiome-immunity axis as a potential avenue to enhance immunotherapy response in cancer patients. As such, this review will discuss the role of the GMB and diet on anti-cancer immunity. We demonstrate that diet affects anti-cancer immunity through both GMB-independent and GMB-mediated mechanisms, and that different diet patterns mold the GMB’s functional and taxonomic composition in distinctive ways. Dietary modulation therefore shows promise as an intervention for improving cancer outcome; however, further and more extensive research in human cancer populations is needed.
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