Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts’ secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations.

The tumor microenvironment (TME) plays an essential role in the development, proliferation, and survival of leukemic blasts in acute myeloid leukemia (AML). Within the bone marrow and peripheral blood, various phenotypically and functionally altered cells in the TME provide critical signals to suppress the anti-tumor immune response, allowing tumor cells to evade elimination. Thus, unraveling the complex interplay between AML and its microenvironment may have important clinical implications and are essential to directing the development of novel targeted therapies. This review summarizes recent advancements in our understanding of the AML TME and its ramifications on current immunotherapeutic strategies. We further review the role of natural products in modulating the TME to enhance response to immunotherapy.

The prognosis of sarcomatoid renal cell carcinoma has changed dramatically with the emergence of immune checkpoint inhibitors. Notably the use of nivolumab and ipilimumab combination therapy has demonstrated promising durable therapeutic response for patients with treatment-naïve sarcomatoid renal-cell carcinoma. We present a case of 45-year-old man with a history of metastatic sarcomatoid renal cell carcinoma treated with nivolumab plus ipilimumab who developed type 1 diabetes mellitus, adrenal insufficiency, thyroiditis/hypothyroidism, and acute interstitial nephritis as a result of immunotherapy.

6534 Background: Social determinants of health (SDOH) can predispose underserved communities to poor cancer outcomes. The CDC has created a Social Vulnerability Index (SVI) score for US counties that integrates four SDOH: socioeconomic status, household composition & disability, minority status & language, and housing type & transportation. Scores range from 0 to 1, with higher values signifying more vulnerability. SVI is a significant determinant of overall mortality, but its association with cancer mortality is unclear. This study aimed to investigate if there is a relationship between SVI and cancer mortality. Methods: CDC WONDER (Wide-Ranging Online Data for Epidemiological Research) was used to estimate age-adjusted mortality rates per 100,000 person-years with 95% CIs for adults > 18 years of age from 3,030 (96%) US counties between 2014-2018 for a composite of three cancers (lung, breast, and colon cancer), individual cancer subtypes, and demographic groups (sex, ethnicity/race, urban/rural classification). Age-adjusted mortality rates were compared across SVI quartiles: 1st (least vulnerable) to 4th (most vulnerable). Linear regression was used to identify the association between the 4th vs. 1st SVI quartile and the odds of being above the median mortality rate for composite cancers, individual cancer subtypes, and demographic groups. Results: Overall, age-adjusted composite cancer mortality rate per 100,000 person-years was 122.9 (lung cancer 82.8, breast cancer 38.1, colon cancer 21.9). The largest concentration of most vulnerable US counties and composite cancer mortality was in the southeastern US. Age-adjusted composite cancer mortality rates increased from 1st to 4th SVI quartiles. Counties in the 4th SVI quartile vs. 1st SVI quartile were significantly more likely to be above the median mortality rate for composite cancer (OR 6.46 [95% CI, 5.16 - 8.08]), lung cancer (6.88 [5.46 - 8.66]), breast cancer (2.77 [2.17 - 3.54]), and colon cancer (6.20 [4.82 - 7.97]). Among all races, non-Hispanic Black adults in the 4th SVI quartile vs. 1st SVI quartile were significantly more likely to be above the median mortality rate for composite cancer (OR 9.46 [95% CI, 6.19 - 14.4]), lung cancer (13.8 [7.87 - 24.1]), breast cancer (5.53 [3.16 - 9.68]), and colon cancer (6.34 [3.69 - 10.9]). Moreover, rural counties in the 4th SVI quartile vs. 1st SVI quartile were between 2- to 8-times more likely to be above the median mortality rate for composite cancer and individual cancer subtypes. Conclusions: This study highlights the most socially vulnerable US counties have higher cancer mortality rates than the least vulnerable US counties. Furthermore, non-Hispanic Black adults and rural counties in the most socially vulnerable category have higher cancer mortality rates than those in the least socially vulnerable category. Additional work is needed to understand how SVI can be used for better resource allocation to help mitigate cancer mortality.

Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the “Warburg Effect” to reduce energy production in AML blasts.

Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease’s progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

Introduction Opioid analgesics are commonly used to manage moderate to severe cancer related pain. However long-term use of opioids has been known to lead to several unintended side effects, including opioid induced hyperalgesia (OIH) which is defined as the paradoxical increase in pain sensitization to pain stimulus following opioid exposure. Currently there are limited reports on the association between patients with cancer and OIH, and this phenomenon is rarely described in patients with leukemia or lymphoma. Here we report a patient with acute promyelocytic leukemia who developed opioid induced hyperalgesia following rapid escalation of opioids. Case report A 36-year-old female being treated for acute promyelocytic leukemia presented with rapidly worsening acute on chronic hip pain requiring increasing opioid requriements. Given the rapid escalation of opioid dose with minimal response and physical exam findings consistent with allodynia/hyperalgesia a diagnosis of opioid induced hyperalgesia was made. Management and outcome Following recognition of opioid induced hyperalgesia, the patient was managed with opioid rotation and ketamine, which resulted in prompt alleviation of pain. Discussion Opioid induced hyperalgesia is likely an underrecognized phenomenon in patients with cancer-related pain. A high index of clinical suspicion are necessary for diagnosis and proper management of this disease entity.

Capnocytophaga canimorsus is a Gram-negative zoonotic pathogen capable of causing serious infection following dog or cat bite. Infections often manifest as sepsis, fatal septic shock, gangrene, bacteraemia, meningitis and endocarditis. Here we report a case of C. canimorsus bacteraemia complicated by tricuspid valve infective endocarditis and septic pulmonary emboli.