Antibody-drug conjugates: Principles and opportunities.

Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs include their potential additive or synergistic effects of the innate backbone antibody and cytotoxic effects of the payload on tumors without the severe toxic side effects often associated with traditional chemotherapy. Recent advances in identifying new targets with tumor-specific expression, along with improved bioactive payloads and novel linkers, have significantly expanded the scope and optimism for ADCs in cancer therapeutics. In this paper, we will first provide a brief overview of antibody specificity and the structure of ADCs. Next, we will discuss the mechanisms of action and the development of resistance to ADCs. Finally, we will explore opportunities for enhancing ADC efficacy, overcoming drug resistance, and offer future perspectives on leveraging ADCs to improve the outcome of ADC therapy for cancer treatment.

Endari treatment ameliorates sickle cell-related disruption in intestinal barrier functions and is associated with prolonged survival in sickle cell mice.

BACKGROUND: Endari (L-glutamine) is a conditional amino acid that reduces the frequency of vaso-occlusive crisis (VOC) in sickle cell disease (SCD). AIM: To investigate whether Endari could ameliorate intestinal barrier function and improve survival outcomes in SCD. METHODS: We treated female Townes SCD mice with Endari and evaluated their intestinal barrier functions by measuring the recovery of orally administered fluorescein isothiocyanate (FITC)-conjugated dextran 4 kDa in serum, and serum intestinal fatty acid binding proteins (iFABP) and lipopolysaccharide (LPS) concentrations by ELISA. We also explored the impact the Endari has on the survival of the SCD mice that underwent repeated experimentally-induced VOC. RESULTS: Compared to SCD mice treated with water only, Endari-treated mice showed improved intestinal barrier functions, with decrease in the barrier permeability and reduction in the translocation of lipopolysaccharides from the intestinal lumen into the circulation. These changes occurred after only 4 weeks of Endari treatment. Improved intestinal barrier function was also associated with prolonged survival in Endari-treated SCD mice after repeated experimentally-induced VOC. CONCLUSION: Our findings provide the evidence supporting the beneficial effects of Enadri in improving intestinal barrier function and associated survival outcomes in SCD.

Utilization and outcome disparities in allogeneic hematopoietic stem cell transplant in the United States.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is increasingly being used in the United States (US) and across the world as a curative therapeutic option for patients with certain high-risk hematologic malignancies and non-malignant diseases. However, racial and ethnic disparities in utilization of the procedure and in outcome following transplant remain major problems. Racial and ethnic minority patients are consistently under-represented in the proportion of patients who undergo allo-HSCT in the US. The transplant outcomes in these patients are also inferior. The interrelated driving forces responsible for the differences in the utilization and transplant outcome of the medical intervention are socioeconomic status, complexity of the procedure, geographical barriers, and the results of differences in the genetics and comorbidities across different races. Bridging the disparity gaps is important not only to provide equity and inclusion in the utilization of this potentially life-saving procedure but also in ensuring that minority groups are well represented for research studies about allo-HSCT. This is required to determine interventions that may be more efficacious in particular racial and ethnic groups. Various strategies at the Federal, State, and Program levels have been designed to bridge the disparity gaps with varying successes. In this review paper, we will examine the disparities and discuss the strategies currently available to address the utilization and outcome gaps between patients of different races in the US.

Returning to employment following allogeneic hematopoietic stem cell transplant: A major problem among survivors.

Quality of life (QoL) is an important aspect of cancer survivorship. One of the most acute problems that impact survivors in many aspects of activities of daily living and compromise their QoL is the inability to return to employment following successful cancer therapy. This is most prominent among survivors after allogeneic hematopoietic stem cell transplant (allo-HSCT). More than 50% of the survivors following allo-HSCT remain unemployed one year after the procedure. This problem extends beyond the initial few years; unemployment rates among those who underwent allo-HSCT during their childhoods or adolescence have remained high. The inability to return to employment imposes a financial burden. Survivors following allo-HSCT also experience a multitude of chronic psychosocial complications that may be both contributing and consequential to the inability to return to employment. However, many transplant programs and cancer centers do not have return-to-employment programs. In this review paper, we discuss the prevalence of unemployment following allo-HSCT. We examine the psychosocial symptoms experienced by survivors and how they may affect survivors' ability to return to employment. Finally, we propose a multi-disciplinary multi-pronged occupation-focused approach to address the complex and inter-related psychosocial symptoms to help alleviate the problem.

CRISPR-based precision medicine for hematologic disorders: Advancements, challenges, and prospects.

The development of programmable nucleases to introduce defined alterations in genomic sequences has been a powerful tool for precision medicine. While several nucleases such as zinc-finger nucleases (ZFN), transcriptor activator-like effector nucleases (TALEN), and meganucleases have been explored, the advent of CRISPR/Cas9 technology has revolutionized the field of genome engineering. In addition to disease modeling, the CRISPR/Cas9 technology has contributed to safer and more effective treatment strategies for hematologic diseases and personalized T-cell-based therapies. Here we discuss the applications of the CRISPR technology in the treatment of hematologic diseases, their efficacy, and ongoing clinical trials. We examine the obstacles to their successful use and the approaches investigated to overcome these challenges. Finally, we provide our perspectives to improve this genome editing tool for targeted therapies.

Metabolic syndrome is independently associated with improved overall survival to first-line therapy with immune checkpoint inhibitors in non-small cell lung cancer.

Background: Many co-existing medical conditions may affect the outcome in patients treated with immune checkpoint inhibitors for advanced cancer. There is currently not any information on whether metabolic syndrome (MetS) impacts the clinical outcome in patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell line cancer (NSCLC). Methods: We carried out a single-center retrospective cohort study to determine the effects of MetS on first-line ICI therapy in patients with NSCLC. Results: One hundred and eighteen consecutive adult patients who received first-line therapy with ICIs and had adequate medical record information for the determination of MetS status and clinical outcomes were included in the study. Twenty-one patients had MetS and 97 did not. There was no significant difference between the two groups in age, gender, smoking history, ECOG performance status, tumor histologic types, pre-therapy use of broad-spectrum antimicrobials, PD-L1 expression, pre-treatment neutrophil:lymphocyte ratio, or proportions of patients who received ICI monotherapy or chemoimmunotherapy. With a median follow-up of 9 months (range 0.5-67), MetS patients enjoyed significantly longer overall survival (HR 0.54, 95% CI: 0.31-0.92) (p = 0.02) but not progression-free survival. The improved outcome was only observed in patients who received ICI monotherapy and not chemoimmunotherapy. MetS predicted for higher probability of survival at 6 months (p = 0.043) and 12 months (p = 0.008). Multivariate analysis indicated that, in addition to the known adverse effects of use of broad-spectrum antimicrobials and the beneficial effects of PD-L1 (Programmed cell death-ligand 1) expression, MetS was independently associated with improved overall survival but not progression-free survival. Conclusions: Our results suggest that MetS is an independent predictor of treatment outcome in patients who received first-line ICI monotherapy for NSCLC.

Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease.

Voxelotor is an allosteric haemoglobin (Hb) modulator that binds covalently and reversibly to Hb alpha chain to facilitate improved Hb-O2 affinity and arterial oxygen. It, therefore, reduces the susceptibility of erythrocytes carrying Haemoglobin S to sickle. In this study, we have used GBT1118, an analog of voxelotor, to treat male Townes sickle cell disease (SCD) mice to investigate whether the Hb modulator could attenuate the intestinal pathophysiologic changes associated with SCD. Compared with mice fed with control chow, GBT1118-treated mice showed improvement in the intestinal pathophysiology. These mice exhibited improved small intestinal barrier functions, reduced intestinal microbial density, reduced enterocyte injury, lower serum lipopolysaccharides and smaller spleens. These improvements were observed after only 3 weeks of GBT1118 treatment. Benefits were also observed after experimentally-induced vaso-occlusive crisis (VOC). Recovery from the VOC-induced changes was faster in mice that were treated with GBT1118. The improved small intestinal barrier function was associated with higher expression of genes encoding enterocyte E-cadherin, JAM-A, ZO-1, MUC-2 and occludin while the lower intestinal microbial density associated with higher expression of genes encoding the antimicrobial peptides defensin-α 1 and defensin-α 4. Our findings provide the evidence to support the beneficial effects of GBT1118 in SCD-related intestinal pathophysiology.

Intestinal barrier functions in hematologic and oncologic diseases.

The intestinal barrier is a complex structure that not only regulates the influx of luminal contents into the systemic circulation but is also involved in immune, microbial, and metabolic homeostasis. Evidence implicating disruption in intestinal barrier functions in the development of many systemic diseases, ranging from non-alcoholic steatohepatitis to autism, or systemic complications of intestinal disorders has increased rapidly in recent years, raising the possibility of the intestinal barrier as a potential target for therapeutic intervention to alter the course and mitigate the complications associated with these diseases. In addition to the disease process being associated with a breach in the intestinal barrier functions, patients with hematologic and oncologic diseases are particularly at high risks for the development of increased intestinal permeability, due to the frequent use of broad-spectrum antibiotics and chemoradiation. They also face a distinct challenge of being intermittently severely neutropenic due to treatment of the underlying conditions. In this review, we will discuss how hematologic and oncologic diseases are associated with disruption in the intestinal barrier and highlight the complications associated with an increase in the intestinal permeability. We will explore methods to modulate the complication. To provide a background for our discussion, we will first examine the structure and appraise the methods of evaluation of the intestinal barrier.

Chronic graft-versus-host disease in pediatric patients: Differences and challenges.

Despite the use of high-resolution molecular techniques for tissue typing, chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplant. cGVHD adversely affects the life-expectancy and quality of life. The latter is particularly important and functionally relevant in pediatric patients who have a longer life-expectancy than adults. Current laboratory evidence suggests that there is not any difference in the pathophysiology of cGVHD between adults and pediatric patients. However, there are some clinical features and complications of the disease that are different in pediatric patients. There are also challenges in the development of new therapeutics for this group of patients. In this review, we will discuss the epidemiology, pathophysiology, clinical features and consequences of the disease, and highlight the differences between pediatric and adult patients. We will examine the current treatment options for pediatric patients with moderate to severe cGVHD and discuss the challenges facing therapeutic development for cGVHD in the pediatric population.

Radioimmunoconjugates in the age of modern immuno-oncology.

Immunotherapy was first investigated as a therapeutic option for treating cancer more than a century ago. During this period, it has gone through numerous disappointments when the successes obtained in the laboratory were not matched clinically. However, recent advances in immuno-oncology have provided the impetus to revisit this therapeutic option. Unlike previous efforts, modern immunotherapy is now a realistic and formidable therapeutic option for patients with relapsed/refractory malignancies. Unfortunately, most of the successes obtained thus far have primarily been in patients with hematologic malignancies. While the results of immunotherapy with immune check-point inhibitors for solid tumors such as non-small cell lung cancer and melanoma are encouraging, more effective treatment methods are desirable. Many intrinsic and extrinsic factors pose as obstacles to successful immunotherapy of solid tumors. They include heterogeneity of tumor antigens, limitation in the trafficking and accessibility of the effector mechanisms to the tumor sites, the adverse anti-inflammatory tumor microenvironment, and the on-target off tumor and off-target off-tumor effects of some of these approaches. In this review, we will discuss these obstacles and examine the evidence that support the notion that radioimmunotherapy, using radioimmunoconjugates, may be the answer to overcome these obstacles in patients with metastatic cancer. Finally, we will discuss how the efficacy of radioimmunotherapy using radioimmunoconjugates might further be harnessed to maximize successes in these patients.

Piperacillin/Tazobactam and Meropenem Use Increases the Risks for Acute Graft Rejection Following First Kidney Transplantation.

Many broad-spectrum antibiotics (BSA) alter the intestinal microbiome that regulates adaptive immune responses. We hypothesized that BSA use before and early after kidney transplant may affect acute graft rejection (AGR). We carried out a retrospective cohort study on all patients who underwent kidney transplants in our institution. Patient demographics, clinical data, diagnosis, and treatment history were collected. Antibiotic use within 2 months prior to transplant and during the hospital admissions for transplant, as well as antibiotic types were recorded. A total of 357 consecutive first transplants were included for analysis. Median age was 52 years (range 7-76). A total of 67 patients received living donor and 290 deceased donor kidneys. A total of 19 patients received BSA within two months prior to transplant and 55 patients during the hospital admission for the transplant. With a median follow-up of 1270 days, 38 episodes of biopsy-proven AGR were recorded. There was no difference in the AGR rates during the first year between patients who received BSA and those who did not. However, the use of piperacillin/tazobactam or meropenem (PM) was associated with increased risks for the development of AGR, irrespective of the source of the donor grafts. Time to development of AGR was also shorter. Our data, therefore, suggest that the use of PM BSA prior to and immediately after kidney transplant increases the risks for AGR.

L-glutamine for sickle cell disease: more than reducing redox.

Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD + + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD. Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy.

Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice.

Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases using fecal microbiota transplant (FMT). It is therefore not surprising that use of FMT, especially for treating relapsed/refractory Clostridioides difficile infections (CDI), has increased over the last decade. Due to the complexity associated with and treatment for these diseases, patients with hematologic and oncologic diseases are particularly susceptible to complications related to altered intestinal microbial composition. Therefore, they are an ideal population for exploring FMT as a therapeutic approach. However, there are inherent factors presenting as obstacles for the use of FMT in these patients. In this review paper, we discussed the principles and biologic effects of FMT, examined the factors rendering patients with hematologic and oncologic conditions to increased risks for relapsed/refractory CDI, explored ongoing FMT studies, and proposed novel uses for FMT in these groups of patients. Finally, we also addressed the challenges of applying FMT to these groups of patients and proposed ways to overcome these challenges.

Genes modulating intestinal permeability and microbial community are dysregulated in sickle cell disease.

Based on previous studies showing abnormalities in the intestinal pathophysiology characterized by disruption in the gut barrier functions, and alteration in the intestinal microbial load and composition, we set out in the study to examine the expression of genes that might be involved in mediating these changes in Townes sickle cell disease (SCD) mice at 6 months old compared to non-SCD control mice. Using qPCR on total RNA isolated from the intestine, we found downregulation of the TJ genes JAM-A, Occludin, and ZO-1 in both the small intestine and colon. E-Cadherin and MUC2 were also downregulated. In contrast, gene encoding claudin-2 that mediates increase permeability to water and ions was upregulated in the small intestine. Claudin-2 upregulation is usually also associated with ongoing inflammation. Intestinal epithelium also includes Paneth cells that produce antimicrobial peptides (AMPs) that regulate intestinal microbial community. We also found that the expression of the genes encoding the AMPs defensin-α4 was reduced in the small intestine and colon and defensin-α1 in the colon in the SCD mice. Our findings are novel and provide direction for further studies into the characteristics and mechanisms of the intestinal pathophysiologic changes observed in SCD.

l-glutamine, crizanlizumab, voxelotor, and cell-based therapy for adult sickle cell disease: Hype or hope?

For more than two decades, hydroxyurea was the only therapeutic agent approved by the Food and Drug Administration (FDA) for sickle cell disease (SCD). Although curative allogeneic hematopoietic stem cell transplants (allo-HSCT) were also available, only very few patients underwent the procedure due to lack of matched-related donors. However, therapeutic options for SCD patients increased dramatically in the last few years. Three new agents, l-glutamine, crizanlizumab, and voxelotor, were approved by the FDA for use in SCD patients. The number of SCD patients who underwent allo-HSCT also increased as a result of advances in the prevention of graft failure and graft-versus-host disease from using mismatched donor HSC. More recently gene therapy was made available on clinical trials. The increased treatment options for SCD have led to a sense of optimism and excitement among many physicians that these new approaches would alter the clinical course and disease burden. Although these newer agents do provide hope to SCD patients, the hyped-up responses need to be evaluated in the context of reality. In this review, we will discuss and compare these new agents and cell-based therapy, evaluate their clinical and economic impacts, and examine their roles in reducing the disease burden.

Intestinal pathophysiological abnormalities in steady state and after vaso-occlusive crisis in murine sickle cell disease.

We showed in the present study that, not unlike in adult patients with sickle cell disease (SCD), Townes mice exhibit increases in serum intestinal fatty acid binding proteins and lipopolysaccharides (LPS), together with a breach in the intestinal barrier. These abnormalities increased rapidly after the induction of vaso-occlusive crisis (VOC). We also confirmed higher intestinal microbial density in SCD. These findings support the concept that SCD and/or its complications, and not hospitalisation or medications, are responsible for the intestinal pathophysiological changes. The present results provide the basis for use of Townes mice to further elucidate the mechanistic relationship between intestinal pathophysiology and VOC.

Sperm protein 17 targeting for epithelialovarian cancer treatment in the eraof modern immunoengineering.

Due to the vague symptomatology of the disease and a lack of effective screening methods, most patients with epithelial ovarian cancer (EOC) present late in their disease. Despite advances in chemotherapeutic agents, the prognosis of these patients has uniformly been extremely poor. Although cisplatin-based chemotherapy regimens induce responses in most of these patients, the patients invariably experience disease progression or relapses. In an attempt to improve the treatment outcome using a different therapeutic approach, immunotherapy was investigated nearly 20 years ago. Many tumor antigens that are potentially suitable for specific immunotherapy were identified, and many immunotherapeutic approaches were attempted. However, although some responses were observed, the results from clinical studies were generally disappointing. Recent advances in immunoengineering and successes observed among patients treated for refractory/relapsed hematologic malignancies have rekindled the interest to revisit specific cellular immunotherapy in EOC. In this review, we provide the rationale for immunotherapy of EOC, discuss the results of some of the historical studies on the use of cellular immunotherapy in EOC, outline the principles of modern immunoengineering that could be applied to treat the disease, and propose the re-evaluation of the cancer-testis antigen, Sperm protein 17, for targeting by using modern immunoengineering technology.

Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT SELEction and Timing Based on Sickle Cell-Related Multiple Chronic Conditions.

Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age. On the other hand, the dilemma facing the patients and families is how acceptable HSCT that carries some mortality risks to them. We have analyzed the chronic conditions due to SCD in 449 patients to determine whether SCD-related multiple chronic conditions (MCC) can be risk-stratified to identify the group of patients predicted to not only have shortened lifespans but also functional limitation and poor quality of life so that these at-risk patients can be offered HSCT early and before MCC develops. We identified that the age of onset of the first SCD-related chronic conditions strongly predicted for the risks for disease-related MCC. SCD patients who suffered their first disease-related chronic condition before age 30 years developed MCC at a rate of 19.1 times faster than those at a later age. These patients are therefore high-risk patients and should be offered HSCT early in the course of their disease before multiple organ damage intervenes, even if matched-related donors are not available. This patient selection and timing approach provides a forum for an easy-to-understand and real-time discussion, including the choice of donor type, with SCD patients and families when considering HSCT.

Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events.

Painful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.

Allogeneic hematopoietic stem cell transplant for sickle cell disease: The why, who, and what.

Allogeneic hematopoietic stem cell transplants (allo-HSCTs) from matched-related donors (MRDs), mismatched-related donors (MMRDs), and matched-unrelated donors (MUDs) are increasingly being used to treat sickle cell disease (SCD) in both pediatric and adult patients. The overall results have been extremely encouraging, especially if a MRD is available and the transplant being performed before the age of 13. Although there is a general consensus that patients with high-risk SCD, even in adults and irrespective of donor characteristics, should be offered allo-HSCT, the debates on optimal patient selection and timing of transplant have yet to be resolved. Unlike patients with hematologic malignancies, there are also a number of clinical issues that require to be addressed in patients with SCD undergoing allo-HSCT. In this review, we will discuss the reasons allo-HSCT should be offered more widely to patients with SCD, the challenges facing physicians in patient selection and timing of transplant, and the awareness of and solutions to prevent the complications that are unique or more common in SCD undergoing allo-HSCT.