Citations

575 Background: Cholangiocarcinoma (CCA) is a lethal hepatobiliary adenocarcinoma with increasing incidence and poor outcomes. Treatment success has been hindered by resistance, and new therapeutic strategies are necessary. The Src-family tyrosine kinase, LCK, activates Yes-associated protein (YAP), a known oncogene in CCA. While YAP has been historically difficult to target, we recently described LCK inhibition as a potential therapeutic option in CCA. We probed the LCK interactome employing biotinylation site identification technology (BioSITe) to discover molecular co-dependencies in the LCK-YAP axis. Methods: LCK-deficient HuCCT1, wild-type HuCCT1, and wild-type RBE cells were transfected with pEF-LCK-TurboID and used to reveal protein-protein interactions. Biotinylated peptides were enriched using anti-biotin antibodies followed by mass spectrometry analysis. Co-immunoprecipitation (Co-IP) was used to confirm interactions between LCK and identified interactors. Phosphoproteome profiling of human CCA tumors and patient derived xenografts was conducted to identify active kinase signatures in CCA. Tyrosine phosphorylated peptides were enriched using anti-phosphotyrosine antibody beads and analyzed by high-resolution mass spectrometery/liquid chromatography. Immunoblot analysis of HuCCT1 and LCK-deficient HuCCT1 cells was used to map the mechanistic interaction between LCK and epidermal growth factor receptor, EGFR. Inhibitors of EGFR and LCK, afatinib and NTRC 0652-0, respectively, were tested in vitro on human and murine CCA cell lines. Cell viability was determined with CellTiter-Glo; Calcusyn software was used to determine synergistic drug effects. Results: We discovered intracellular interactors of LCK in CCA using BioSITe. We identified both known and novel LCK interactors, including EGFR. Given that EGFR functions as a molecular driver of tumorigenesis and is increasingly recognized as a biomarker of resistance in a variety of tumors, we performed a phosphoproteomic evaluation of CCA tumors in which activated EGFR was identified by the presence of EGFR-Y1092, Y1197, and Y1172 phosphorylation. EGFR phosphorylation decreased under conditions of genetic LCK knock out and inhibition by NTRC 0652-0. Co-IP confirmed the interaction of EGFR with LCK. EGFR-Y1092 phosphorylation was downregulated with genetic knockout of LCK by immunoblot. Finally, EGFR inhibition was evaluated as a therapeutic strategy utilizing afatinib. Effects on cell viability were noted in both human and murine CCA cells. Afatinib and NTRC 0652-0 demonstrated a synergistic effect in vitro, with calculated combination indices of 0.007 – 0.790. Conclusions: A novel interaction between EGFR and LCK in CCA was identified using an unbiased proximity-dependent biotinylation technique. Dual blockade of LCK and EGFR is synergistic in CCA and may be a viable therapeutic approach for patients.

AbstractPlasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1–196), the 3‐year progression‐free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3‐year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper‐CVAD or auto‐SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

Abstract Multiple myeloma (MM) is a largely incurable hematological malignancy characterized by clonal expansion of plasma cells in bone marrow (BM). Autologous stem cell transplantation (ASCT) remains a standard treatment for MM, allows intensive cytoreduction and induces inflammation in the context of lymphodepletion. We hypothesized that SCT may overcome myeloma-induced immune defects to restore immune-equilibrium. To address this, we developed a model of ASCT for MM using Vk*MYC myeloma. Surprisingly, we demonstrate the induction of T cell-dependent MM control after SCT as recipients of syngeneic BM grafts containing T cells had prolonged survival and reduced tumor burden compared to BM alone. This anti-myeloma activity was independent of γδ T, natural killer (NK) and NK T cells and was dependent on CD4+and CD8+ T cells. MM-primed T cells, harvested from SCT recipients with controlled MM, protected against relapse in secondary recipients and were Vk*MYC clone-specific. Recipients of MM-primed T cells had increased central memory CD8+ T cells and transfer of MM-primed CD8+ T cells was sufficient to prevent relapse. Furthermore, TCR sequencing of CD8+ T cells from mice with controlled MM revealed a higher clonotype overlap relative to MM-free SCT recipients, consistent with MM-specific T cells. Donor IFNγ secretion and signaling was critical to protective immunity and CD8+ T cells from mice with relapsed MM had impaired IFNγ production compared to those with controlled disease. Importantly, IFNγ production was profoundly augmented by CD137 agonist treatment such that majority of mice controlled disease. These data provide new insights into the mechanisms of action of SCT in myeloma and suggest the use of CD137 agonists to prevent relapse.

PURPOSE The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other health care providers on integrative approaches to managing pain in patients with cancer. METHODS The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included pain intensity, symptom relief, and adverse events. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 227 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Among adult patients, acupuncture should be recommended for aromatase inhibitor–related joint pain. Acupuncture or reflexology or acupressure may be recommended for general cancer pain or musculoskeletal pain. Hypnosis may be recommended to patients who experience procedural pain. Massage may be recommended to patients experiencing pain during palliative or hospice care. These recommendations are based on an intermediate level of evidence, benefit outweighing risk, and with moderate strength of recommendation. The quality of evidence for other mind-body interventions or natural products for pain is either low or inconclusive. There is insufficient or inconclusive evidence to make recommendations for pediatric patients. More research is needed to better characterize the role of integrative medicine interventions in the care of patients with cancer. Additional information is available at https://integrativeonc.org/practice-guidelines/guidelines and www.asco.org/survivorship-guidelines .

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5–17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 μg/mL (SD 67) and a median of 22 μg/mL (interquartile range 12–38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Lay SummaryWe demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.