Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies.

The success of immune checkpoint blockade in patients with a wide variety of malignancies has changed the treatment paradigm in oncology. However, combination therapies with immune checkpoint blockade will be needed to overcome resistance and broaden the clinical utility of immunotherapy. Here we discuss a framework for rationally designing combination therapy strategies based on enhancing major discriminatory functions of the immune system that are corrupted by cancer-namely, antigenicity, adjuvanticity, and homeostatic feedback inhibition. We review recent advances on how conventional genotoxic cancer therapies, molecularly targeted therapies, epigenetic agents, and immune checkpoint inhibitors can restore these discriminatory functions. Potential barriers that can impede response despite combination therapy are also discussed.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. METHODS: This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). RESULTS: Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). CONCLUSIONS: Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate-risk and high-risk head and neck squamous cell carcinoma.

BACKGROUND: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. RESULTS: Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. CONCLUSIONS: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.

Adding Adjuvant Systemic Treatment after Neoadjuvant Therapy in Breast Cancer: Review of the Data.

PURPOSE OF REVIEW: Residual disease after neoadjuvant chemotherapy is a poor prognostic factor; however, proven strategies to reduce recurrence risk and improve overall survival in this patient population are limited. Previous studies of residual disease have illustrated the importance of tumor intrinsic subtypes in treatment response and mechanisms of resistance. This review summarizes the rationale for various therapeutic approaches as well as completed and ongoing clinical trials for this high-risk group of patients. RECENT FINDINGS: Regimens utilizing additional chemotherapy and targeted therapies (such as PARP inhibitors or bisphosphonates) have met with limited efficacy. Notably, a recently published randomized study of capecitabine in patients with residual disease demonstrated an improvement in disease-free survival and overall survival. While the results for capecitabine are promising, particularly for patients with triple-negative disease, the generalizability of these findings is an open question. Meanwhile, ongoing trials with novel agents that target specific tumor subtypes and the biology of residual disease may improve outcomes for other patient populations.

Sinonasal Squamous Cell Carcinoma Survival Outcomes Following Induction Chemotherapy vs Standard of Care Therapy.

OBJECTIVE: To compare oncologic outcomes in sinonasal squamous cell carcinoma (SNSCC) treated with standard of care (SOC) definitive therapy, consisting of surgery or chemoradiotherapy, vs induction therapy followed by definitive therapy. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary care hospital. METHODS: The medical records of patients with biopsy-proven SNSCC treated between 2000 and 2020 were reviewed for demographics, tumor characteristics, staging, treatment details, and oncologic outcomes. Patients were matched 1-to-1 by age, sex, and cancer stage according to treatment received. Time-to-event analyses were conducted. RESULTS: The analysis included 26 patients with locally advanced SNSCC who received either induction therapy (n = 13) or SOC (n = 13). Baseline demographics, Charlson Comorbidity Index, and median follow-up time were well balanced. Weekly cetuximab, carboplatin, and paclitaxel were the most common induction regimen utilized. Tolerance and safety to induction were excellent. Objective responses were observed in 11 of 13 patients receiving induction. No difference in disease-free survival was found between the induction and SOC groups at 1 or 3 years. However, when compared with SOC, induction therapy resulted in significant improvement in overall survival at 2 years (100% vs 65.3%, P = .043) and 3 years (100% vs 48.4%, P = .016) following completion of definitive therapy. Two patients in the SOC group developed metastatic disease, as compared with none in the induction group. CONCLUSIONS: Induction therapy was safe and effective. When compared with SOC, induction therapy improved 3-year overall survival.

Functional analysis of the Cdk7.cyclin H.Mat1 complex in mouse embryonic stem cells and embryos.

The trimeric Cdk7.cyclin H.Mat1 complex functions in cell cycle regulation, as the Cdk-activating kinase, and in transcription, as a module of the general transcription factor TFIIH. As a component of TFIIH, Cdk7 phosphorylates serines 5 and 7 of the carboxyl-terminal domain of RNA polymerase II and can also directly phosphorylate transcription factors to regulate gene expression. Here we have investigated the function of the Cdk7.cyclin H.Mat1 complex in murine embryonic stem (ES) cells and preimplantation embryos to determine whether it regulates the unique cell cycle structure and transcriptional network of pluripotent cells. We demonstrate that depletion of cyclin H leads to differentiation of ES cells independent of changes in cell cycle progression. In contrast, we observed that developmental genes are acutely up-regulated after cyclin H down-regulation, likely perturbing normal ES self-renewal pathways. We further demonstrate that Spt5, a known phosphorylation target of Cdk7, similarly regulates ES pluripotency and gene expression. Consistent with its function in ES cells, cyclin H depletion from mouse embryos also leads to defects in the expansion of the inner cell mass of blastocysts, a transient pluripotent stem cell population in vivo. Our findings indicate that cyclin H has an essential function in promoting the self-renewal of the pluripotent stem cells of blastocyst stage embryos. Collectively, these studies demonstrate a critical and novel role for cyclin H in maintaining ES cell identity and suggest that cyclin H has important functions in early embryonic development.

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses.

Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality.

A case of metastatic NUT carcinoma with prolonged response on gemcitabine and nab-paclitaxel.

BACKGROUND: NUT carcinoma is an aggressive malignancy characterized by translocations in the NUTM1 gene. There are currently no consensus treatment recommendations for NUT carcinomas. METHODS: Here, we describe the case of a previously healthy male diagnosed with NUT carcinoma after presenting with sinus pressure, found to have a sinonasal mass and distant metastatic disease in the lungs. While pathologic evaluation and immunohistochemistry were consistent with NUT carcinoma, initial genomic profiling did not demonstrate a NUTM1 translocation. RESULTS: Whole transcriptomic RNA sequencing of the tumor revealed a YAP1-NUTM1 fusion. Based on an in vitro drug sensitivity screen, the patient was treated with gemcitabine and nab-paclitaxel, achieving a partial response that persisted for 9 months. CONCLUSIONS: Unbiased transcriptomic sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab-paclitaxel is a well-tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma.

Consolidation With Pembrolizumab and Nab-Paclitaxel After Induction Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Induction with four cycles of platinum-based chemotherapy was the standard of care for metastatic non-small cell lung cancer (NSCLC) until the approval of immune checkpoint blockade (ICB) in the first-line setting. Switch maintenance therapy has shown promise in improving survival by exposing patients to novel, non-cross-resistant agents earlier in their treatment course. METHODS: We performed this open-label, three-arm, randomized phase II study (NCT02684461) to evaluate three sequences of consolidation with pembrolizumab and nab-paclitaxel in patients without progressive disease post induction chemotherapy. Consolidation was either sequential with pembrolizumab for four cycles followed by nab-paclitaxel for four cycles (P→A), nab-paclitaxel followed by pembrolizumab (A→P), or concurrent nab-paclitaxel and pembrolizumab for four cycles (AP). RESULTS: Twenty patients were randomized before the study was closed early due to the approval of first-line checkpoint inhibitors. We found that consolidation is feasible and well tolerated, with 30% of patients experiencing grade 3 toxicity. The median progression-free survival and OS in months (95% CI) in P→A were 10.1 (1.5-NR), 27.6 (1.7-NR); 8.4 (1.2-9.0), 12.7 (4.4-NR) in A→P; and 10.2 (5.1-NR), NR. Quality of life as measured by FACT-L improved in the majority of patients during the course of the study. CONCLUSION: Sequential and concurrent consolidation regimens are well tolerated and have encouraging overall survival in patients with metastatic NSCLC.

Advances in the Treatment of Non-Small Cell Lung Cancer: Immunotherapy.

Clinical development of immune checkpoint blockade has dramatically changed the treatment paradigm and prognosis for patients with non-small cell lung cancer. Immune checkpoint blockade with PD-1 and PD-L1 antibodies generates clinically significant, durable responses in patients with advanced non-small cell lung cancer. These agents are approved for first- and second-line treatment, either as single agents or in combination with chemotherapy and angiogenesis inhibitors. Although the toxicity profile of these treatments is favorable, a unique set of immune-mediated adverse events, such as pneumonitis, has been observed. Broader use of these agents is improving survival for patients with advanced lung cancer.

Genetic analysis of invasive carcinoma arising in intraductal oncocytic papillary neoplasm of the pancreas.

A case of intraductal oncocytic papillary neoplasm of the pancreas, with the rare progression to invasive carcinoma, is described. The intraductal oncocytic papillary neoplasm component had the features typical of this entity, with stratified layers of oncocytic cuboidal tumor cells growing in papillary and pseudopapillary arrangements within dilated pancreatic ducts. The invasive carcinoma formed a discrete fleshy tumor with well-circumscribed borders. The invasive carcinoma grew in solid lobules, subdivided by fine fibrovascular septae into predominantly organoid and trabecular growth patterns. Molecular analysis showed no loss of heterozygosity for microsatellite markers at the tumor suppressor loci of TP53, CDKN2A (p16/INK4A), and MADH4 (Smad4/DPC4) in the invasive carcinoma, although loss of heterozygosity was detected at one CDKN2A marker in the intraductal component. DNA sequencing of polymerase chain reaction amplification products of exons 1 and 2 of the CDKN2A gene showed no mutation in either tumor component. TP53 immunohistochemistry showed no increased levels of staining, consistent with the presence of wild-type gene product. Polymerase chain reaction and DNA sequencing showed no mutation of codons 12 and 13 of the KRAS proto-oncogene. These results suggest that intraductal oncocytic papillary neoplasm is a neoplasm with genetic changes that are distinct from typical pancreatic adenocarcinoma. The lack of mutation in these genes may be an explanation for the typically indolent clinical behavior of intraductal oncocytic papillary neoplasms.

Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.

Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1alpha and HIF-2alpha, and overexpression of HIF-2alpha in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2alpha during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1alpha versus HIF-2alpha must be elucidated. We demonstrate here that mice lacking HIF-2alpha in myeloid cells (Hif2aDelta/Delta mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2alpha directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2aDelta/Delta mice displayed reduced TAM infiltration in independent murine hepatocellular and colitis-associated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2alpha modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2alpha as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.

Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model.

Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and are overexpressed in a number of tumors. Although HIF1alpha and HIF2alpha share a high degree of sequence homology, recent work has shown that the two alpha subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFalpha subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2alpha expression and Hif1alpha(+/-) mice to homozygotes for the R270H mutation in p53. Here, we report that p53(R270H/R270H) mice, which have not been previously described, develop a unique tumor spectrum relative to p53(R270H/-) mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1alpha significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1alpha levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. These observations uncover a novel role for HIF1alpha in Notch pathway activation during T-cell lymphomagenesis.

The impact of O2 availability on human cancer.

During the past century it has been established that regions within solid tumours experience mild to severe O(2) deprivation owing to aberrant vascular function. These hypoxic regions are associated with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumour cell metabolism, angiogenesis, growth and metastasis. The central role played by intra-tumoural hypoxia and HIF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.