Comprehensive review on the elaboration of payloads derived from natural products for antibody-drug conjugates.

Antibody-drug conjugates (ADCs) have arisen as a promising class of biotherapeutics for targeted cancer treatment, combining the specificity of monoclonal antibodies with the cytotoxicity of small-molecule drugs. The choice of an appropriate payload is crucial for the success development of ADCs, as it determines the therapeutic efficacy and safety profile. This review focuses on payloads derived from natural products, including cytotoxic agents, DNA-damaging agents, and immunomodulators. These offer several advantages such as diverse chemical structures, unique mechanism of actions, and potential for improved therapeutic index. Challenges and opportunities associated with their development were highlighted. This review underscores the significance of natural product payloads in the elaboration of ADCs, which serves as a valuable resource for researchers involved in developing and optimizing next-generation ADCs for cancer treatment.

Soluble CD4 and low molecular weight CD4-mimetic compounds sensitize cells to be killed by anti-HIV cytotoxic immunoconjugates.

IMPORTANCE: HIV infection can be effectively treated to prevent the development of AIDS, but it cannot be cured. We have attached poisons to anti-HIV antibodies to kill the infected cells that persist even after years of effective antiviral therapy. Here we show that the killing of infected cells can be markedly enhanced by the addition of soluble forms of the HIV receptor CD4 or by mimics of CD4.

Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

These joint European Association of Neuro-Oncology (EANO)­European Society for Medical Oncology (ESMO) recommendations for the diagnosis and treatment of leptomeningeal metastasis (LM) from solid tumours provide an update of the first joint EANO­ESMO guideline1 and complement the EANO­ESMO guideline on brain metastasis from solid tumours.2 LM is defined as the spread of tumour cells within the leptomeninges and the subarachnoid space. The present recommendations address LM from extra-central nervous system (CNS) solid tumours, but do not address LM from primary brain tumours, lymphoma or leukaemia. The recommendations cover diagnosis, treatment and follow-up, but do not cover the differential diagnosis, treatment-related adverse events (AEs) or supportive or palliative care in detail. The authors propose diagnostic criteria and assign levels of certainty to the diagnosis of LM in order to provide guidance regarding when to treat versus when to intensify diagnostic efforts and which patients to include in clinical trials. The authors also provide a pragmatic treatment algorithm based on LM subtypes. Supporting evidence for this guideline focuses on LM-specific data with reference to the EANO­ESMO guideline on brain metastasis from solid tumours2 when LM-specific data are not available. Given the low level of evidence available, recommendations are often based on expert opinion and consensus rather than on evidence from informative clinical trials. Still, these EANO­ESMO multidisciplinary recommendations serve as a valuable source of information for physicians and other health care providers, as well as for patients and relatives.

Peripheral CD4 memory T cells predict the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer.

Immune checkpoint inhibitors have significantly improved the prognosis in patients with non-small cell lung cancer, compared with cytotoxic agents. However, the prediction of treatment response is often difficult, even after assessing the tumor programmed death-ligand 1 expression. We conducted this observational study to analyze the association between the differentiation of peripheral CD4 + T cells and the efficacy of immune checkpoint inhibitor therapy. We enrolled patients who were diagnosed with non-small cell lung cancer and received immune checkpoint inhibitor therapy between 2020 and 2022. Blood samples were collected at the start of immune checkpoint inhibitor therapy, and the expressions of PD-1, CCR7, and CD45RA in peripheral CD4 + T cells were analyzed by flow cytometry. The association between the findings of flow cytometry and survival after the initiation of the immune checkpoint inhibitor therapy was evaluated. Forty patients with non-small cell lung cancer were enrolled. The Cox proportional hazards model showed that an increased proportion of CD45RA-CD4 + T cells was associated with a reduced risk of progression after adjustment for performance status, tumor programmed death-ligand 1 expression level, mutation status of the epidermal growth factor receptor gene, and combined therapy with cytotoxic agents. The present study showed that the proportion of peripheral CD45RA- CD4 + T cells was associated with progression-free survival after the initiation of immune checkpoint inhibitor therapy, independent of several clinical factors.

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates.

Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors.

Local Drug Delivery Techniques for Triggering Immunogenic Cell Death.

Immunogenic cell death (ICD), a dying state of the cells, encompasses the changes in the conformations of cell surface and the release of damage-associated molecular patterns, which could initiate an adaptive immune response by stimulating the dendritic cells to present antigens to T cells. Advancements in biomaterials, nanomedicine, and micro- and nano-technologies have facilitated the development of effective ICD inducers, but the potential toxicity of these vesicles encountered in drug delivery via intravenous administration hampers their further application. As alternatives, the local drug delivery systems have gained emerging attention due to their ability to prolong the retention of high payloads at the lesions, sequester drugs from harsh environments, overcome biological barriers to exert optimal efficacy, and minimize potential side effects to guarantee bio-safety. Herein, a brief overview of the local drug delivery techniques used for ICD inducers is provided, explaining how these techniques broaden, alter, and enhance the therapeutic capability while circumventing systemic toxicity at the same time. The historical context and prominent examples of the local administration of ICD inducers are introduced. The complexities, potential pitfalls, and opportunities for local drug delivery techniques in cancer immunotherapy are also discussed.

Antibody-Drug Conjugates as a Targeted Therapeutic Approach Across Entities in Oncology.

BACKGROUND: Cancer is no longer treated on the basis of its histological lineage alone; more and more drugs are being developed that are directed toward specific molecular and immunological features. Monoclonal antibodies are one type of selectively acting therapeutic agent. As part of this development, antibody-drug conjugates ("ADCs") have been approved in recent years for the treatment of hematologic and solid malignancies. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed, as well as on papers presented at international congresses of specialist societies such as the European Society for Medical Oncology, the American Society of Clinical Oncology, and the American Association for Cancer Research, and information published on the websites of the European Medicines Agency, the Food and Drug Administration, and the German Joint Federal Committee. RESULTS: The efficacy of the nine ADCs currently approved in the European Union (as of 12/2022) is derived from technical improvements in the conjugation process, the introduction of novel linkers for the covalent binding of cytotoxic agents to the Fc portion of the antibody, and the development of new, potent cytotoxic agents. Compared to conventional cancer therapies, the approved ADCs improve treatment outcomes with respect to tumor remission, time to tumor progression and, in some cases, overall survival by specifically channeling cytotoxic agents into the malignant target cells and thereby limiting, at least to some extent, the exposure of healthy tissue to adverse effects. Various potential side effects still require attention, including venous occlusive disease, pneumonitis, ocular keratopathy, and skin rash. The development of effective ADCs requires the identification of tumor-selective targets to which ADCs can bind. CONCLUSION: ADCs are a novel category of drugs for the treatment of cancer. Their approval is mainly, but not exclusively, based on the favorable findings of randomized, controlled phase III trials. ADCs are already helping to improve the outcomes of treatment for cancer.

Peptide-Drug Conjugates: A New Hope for Cancer Management.

Cancer remains the leading cause of death worldwide despite advances in treatment options for patients. As such, safe and effective therapeutics are required. Short peptides provide advantages to be used in cancer management due to their unique properties, amazing versatility, and progress in biotechnology to overcome peptide limitations. Several appealing peptide-based therapeutic strategies have been developed. Here, we provide an overview of peptide conjugates, the better equivalents of antibody-drug conjugates, as the next generation of drugs for required precise targeting, enhanced cellular permeability, improved drug selectivity, and reduced toxicity for the efficient treatment of cancers. We discuss the basic components of drug conjugates and their release action, including the release of cytotoxins from the linker. We also present peptide-drug conjugates under different stages of clinical development as well as regulatory and other challenges.

Molecular characterization of Helicobacter pylori clinical isolates from Eastern Saudi Arabia.

OBJECTIVES: To describe the frequency of cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) virulence genes and clarithromycin resistance-associated mutations among Helicobacter pylori (H. pylori) clinical isolates from Eastern Saudi Arabia. METHODS: A cross-sectional study was carried out between July 2020 and June 2021 in a tertiary hospital in AL-Khobar, Saudi Arabia. A total of 34 H. pylori isolates were obtained from gastric biopsies of patients with dyspepsia. The existence of the virulence genes was studied by polymerase chain reaction and the gene fragment of the 23s ribosomal subunit (23s rRNA) gene was sequenced. RESULTS: All isolates harbored the CagA gene. Approximately 97.1% (33/34) isolates were positive using the VacA M primer and 91.2% (31/34) isolates were positive using the VacA S primer. The most frequent allelic combination was S2/M2/cag (60%), followed by S1/M2/cag (26.7%), S1/M1/cag (10%), and S2/M1/cag (3.3%). Approximately 6.5% isolates harbored the A2142G mutation and 29% isolates harbored the A2143G mutation. One isolate contained the mutation T2182C. The phylogenetic analysis showed that 58% isolates clustered with the regional and global isolates while the remaining 42% isolates seemed to be specifically circulating in Saudi Arabia. Most of the patients (73.5%) had already underwent a previous H. pylori eradication therapy. CONCLUSION: We showed that there is a regional variation in the frequency of the virulence genes among H. pylori isolates. Additionally, we showed the frequency of 23s rRNA mutations related to clarithromycin resistance in Saudi Arabia.

Case report: Ruxolitinib as first-line therapy for secondary hemophagocytic lymphohistiocytosis in patients with AIDS.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a fatal immunological syndrome resulting from excessive production of inflammatory cytokines. The conventional therapies for HLH, which are based on cytotoxic agents, are not always efficacious and safe, especially in patients with severe immunodeficiency. Ruxolitinib, a strong inhibitor of Janus kinase (JAK) 1/2, has already been evaluated as salvage and first-line therapy for HLH. Despite its promising efficacy and tolerability in the treatment of secondary HLH, the efficacy and safety of ruxolitinib in HLH patients with HIV infection remain to be investigated. Case presentation: Two men (ages: 45 and 58 years) both presented at our hospital with a high fever. They were found to be HIV-positive with severe immunodeficiency and opportunistic infections. Their laboratory tests showed severe pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and increased levels of inflammatory factors and ferritin. Hemophagocytosis was found in the bone marrow, and abdominal computed tomography or ultrasonography showed splenomegaly. Both patients were diagnosed with infection-induced HLH due to severe immunodeficiency. Given they were both highly immunocompromised, we chose ruxolitinib as a first-line treatment alternative to cytotoxic chemotherapy. Rapid remission of clinical symptoms and normalization of laboratory parameters were achieved after ruxolitinib therapy. Neither patient had any associated adverse drug reactions or other laboratory abnormalities. Both patients were eventually discharged and ruxolitinib was discontinued as their disease alleviated, and they did not show signs of relapse during the 3- and 5-month of follow-up examinations. Conclusion: We described two cases of AIDS-related secondary HLH treated with ruxolitinib. Our cases highlight the feasibility of using ruxolitinib as a first-line therapy in patients with HIV infection and secondary HLH. Nevertheless, the safety and efficacy of this novel treatment need to be evaluated in large clinical trials in the future.

[Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer].

As a newly emerged class of anticancer bioagents in the most precise and selectively targeted way, antibody-drug conjugate (ADC) combines the cancer-targeting abilities of monoclonal antibodies with the cytotoxicity potency of payload, delivering highly cytotoxic drug into tumors via 'targeted chemotherapy'. ADC has revolutionized the treatment landscape of human epidermal growth factor receptor 2 positive and triple negative subtypes in breast cancer. Three ADCs have been approved by U. S. Food and Drug Administration with breast cancer indications, including trastuzumab emtansine (T-DM1; also approved in China), trastuzumab deruxtecan (T-DXd, DS-8201) and sacituzumab govitecan (IMMU-132; also approved in China). Antibodies, cytotoxic drug, linker, and conjugation process are implicated in ADC profile, resulting in unique adverse drug reactions and toxicity heterogeneity within ADC class. For example, more attention should be paid to the management of thrombocytopenia, hepatotoxicity, and reductions in left ventricular ejection fraction (LVEF) in patients treated with trastuzumab emtansine; clinical physicians should pay attention to the risk of neutropenia, interstitial lung disease/pneumonitis, and reductions in LVEF when treated with trastuzumab deruxtecan; sacituzumab govitecan most frequently caused neutropenia, anemia and diarrhea requiring close monitor. ADC has generally favorable safety profiles, and dose modifications and/or symptomatic supporting treatment are effective in terms of toxicity management. This consensus aims at providing guidance for clinical oncologists of early detection, regular assessment, timely management and follow-up monitor of ADC-associated adverse reactions/events.

Efficacy and toxicity of antibody-drug conjugates in the treatment of metastatic urothelial cancer: A scoping review.

INTRODUCTION: Metastatic urothelial cancer (mUC) is an aggressive disease with limited overall survival and treatment options. Antibody-drug conjugates (ADCs) were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to monoclonal antibodies (mAbs) and have emerged as new treatment options in mUC, mainly in chemotherapy (CT) and immune-checkpoint inhibitors (ICI)-exposed patients. We aimed to perform a scoping review to assess activity, efficacy, treatment-related adverse events (TRAEs), and impact on quality of life of ADCs in mUC. METHODS: A review of the literature was performed in January 2022 using Pubmed and Embase databases according to the recommendations of the Joanna Briggs Institute. The search method involved querying for the terms "bladder carcinoma" or "urothelial carcinoma" with any of the following: "enfortumab vedotin" (EV), "sacituzumab govitecan" (SG), antibody-drug conjugate. Only prospective clinical trials were included. RESULTS: Ultimately, eleven clinical trials with 1417 patients were selected for inclusion, and five drugs were identified: enfortumab vedotin (EV), sacituzumab govitecan (SG), disitamab vedotin (RC48-ADC), ASG-15ME (anti-SLITRK6), and trastuzumab deruxtecan. The different ADCs have been tested mainly in phase 1 or phase 2 trials, as monotherapy or in combination with ICI. Response rate ranged from 27% with SG in previously treated patients to 73.3% with EV plus pembrolizumab in cisplatin-ineligible patients as first-line treatment. The phase 3 trial, EV-301, confirmed EV superiority over investigator-chosen CT after failure to platinum-based CT and ICI, improving overall survival (12.88 vs. 8.97 months; HR 0.70; 95% CI, 0.56-0.89; P=0.001). TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of grade 3 ≥ events ranging from 51.4 to 73.5% in different trials. TRAEs of particular interest related to EV were rash, neuropathy, and hyperglycemia. SG was associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life but an improvement in pain symptoms compared to the control arm. CONCLUSIONS: ACDs represent a new therapeutic option for the treatment of mUC. Level-1 evidence has already been achieved by EV in the post-CT and post-ICI settings. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Clinicians should be aware of possible adverse events and their optimal management.

Combination of microtubule targeting agents with other antineoplastics for cancer treatment.

Microtubule targeting agents (MTAs) have attracted extensive attention for cancer treatment. However, their clinical efficacies are limited by intolerable toxicities, inadequate efficacy and acquired multidrug resistance. The combination of MTAs with other antineoplastics has become an efficient strategy to lower the toxicities, overcome resistance and improve the efficacies for cancer treatment. In this article, we review the combinations of MTAs with some other anticancer drugs, such as cytotoxic agents, kinases inhibitors, histone deacetylase inhibitors, immune checkpoints inhibitors, to overcome these obstacles. We strongly believe that this review will provide helpful information for combination therapy based on MTAs.

Current trends in chemotherapy for advanced ovarian cancer.

Chemotherapy for advanced ovarian cancer has progressed over the past several decades with the introduction of cytotoxic agents. Various methods, including single agents, combination therapy and changes in the method of administration, have been validated in many clinical trials and have been combined in an attempt to improve the prognosis of advanced ovarian cancer. In recent years, molecular-targeted agents have been added to cytotoxic agents as a treatment option for maintenance therapy; however, their efficacy has been limited, and further development of treatment options is expected. The advent of poly(ADP-ribose) polymerase inhibitors has considerably improved prognosis and has affected treatment strategies for advanced ovarian cancer over the past few years. With the addition of the recently introduced immune checkpoint inhibitors, future treatment strategies for advanced ovarian cancer may become more complex. In this review, we introduce the latest advances in chemotherapy for advanced ovarian cancer and discuss future perspectives.

Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution.

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients' prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones' survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host's immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.

Simultaneous Pseudoprogression and an Immune-related Adverse Event of Pulmonary Pleomorphic Carcinoma after Combined Therapy with Cytotoxic Anticancer Agents and Immune Checkpoint Inhibitor.

Pulmonary pleomorphic carcinoma is rare among lung tumors. Pulmonary pleomorphic carcinoma is resistant to chemotherapy. However, treatment with taxane anticancer agents and immune checkpoint inhibitors has been reported to be effective. When using immune checkpoint inhibitors, pseudoprogression and true progression are difficult to distinguish, and immune-related adverse events (irAEs) are common. We herein report a patient with simultaneous pseudoprogression and irAEs after combined therapy with cytotoxic agents and an immune checkpoint inhibitor for pulmonary pleomorphic carcinoma. Immune checkpoint inhibitors are effective against pulmonary pleomorphic carcinoma, but patients should be monitored for pseudoprogression and irAEs.

Bacteria-Elicited Specific Thrombosis Utilizing Acid-Induced Cytolysin A Expression to Enable Potent Tumor Therapy.

Given the special microenvironment of solid tumors, live microorganisms have emerged as drug delivery vehicles and therapeutic agents. Here, an acid-induced therapeutic platform is constructed using attenuated Escherichia coli to express the cytolysin A protein. The bacteria can target and colonize tumor tissues without causing notable host toxicity. Bacterial infection can disrupt blood vessels and trigger thrombosis in tumor tissues, resulting in the cut-off of nutrient supply to tumor cells and the arrest of tumor growth. The expression of cytolysin A induced by the acidic tumor microenvironment further strengthens thrombosis and provides a complementary therapeutic option due to its pore-forming function. In a xenograft mouse tumor model, this strategy reduces tumor proliferation by 79% and significantly prevents tumor metastasis, thus paving a new avenue for bacteria-based tumor therapy.

ABCs of ADCs in management of relapsed/refractory diffuse large B-cell lymphoma.

In the past 5 years, 3 chimeric antigen receptor (CAR) T-cell therapies, 2 antibody-drug conjugates (ADCs), 1 CD19-directed monoclonal antibody, and 1 exportin-1 inhibitor have been approved by the Food and Drug Administration for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The noncellular therapies received accelerated approval based on the overall response rate in clinical trials that differ in multiple aspects of the patient populations enrolled, including age, performance status, prior lines of therapy, and inclusion of patients with primary refractory DLBCL, transformed lymphoma, or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. ADCs approved for DLBCL differ in target antigen, antibody structure, linker, and cytotoxin, which results in a different safety and efficacy profile. Here, we comprehensively review the current knowledge of recently approved and emerging strategies for the management of R/R DLBCL with a focus on ADCs.

The identification of the anthracycline aclarubicin as an effective cytotoxic agent for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, mainly due to its delayed diagnosis and lack of effective therapeutic options. Therefore, it is imperative to find novel treatment options for PDAC. Here, we tested a series of conventional chemotherapeutics together with anthracycline compounds as single agents or in combination, determining their effectivity against established commercial and patient-derived, low-passage PDAC cell lines. Proliferation and colony formation assays were performed to determine the anticancer activity of anthracyclines; aclarubicin and doxorubicin, on commercial and patient-derived, low-passage PDAC cell lines. In addition, the effect of standard-of-care drugs gemcitabine and individual components of FOLFIRINOX were also investigated. To evaluate which mechanisms of cell death were involved in drug response, cleavage of poly(ADP-ribose)polymerase was evaluated by western blot. Aclarubicin showed superior antitumor activity compared to other anthracyclines and standard of care drugs (gemcitabine and individual components of FOLFIRINOX) in a patient-derived, low-passage PDAC cell line and in commercial cell lines. Importantly, the combination of gemcitabine and aclarubicin showed a synergistic effect at a dose range where the single agents by themselves were ineffective. In parallel, evaluation of the antitumor activity of aclarubicin demonstrated an apoptotic effect in all PDAC cell lines. Aclarubicin is cytotoxic for commercial and patient-derived low-passage PDAC cell lines, at doses lower than peak serum concentrations for patient treatment. Our findings support a (re)consideration of aclarubicin as a backbone of new combination regimens for pancreatic cancer patients.

Bacillus thuringiensis: From biopesticides to anticancer agents.

Bacillus thuringiensis (Bt) is a ubiquitous bacterium that produces several proteins that are toxic to different invertebrates such as insects, nematodes, mites, and also some protozoans. Among these, Cry and Cyt proteins are most explored as biopesticides for their action against agricultural pests and vectors of human diseases. In 2000, a group of researchers from Japan isolated parasporal inclusion proteins from B. thuringiensis, and reported their cytotoxic action against human leukemia. Later, other proteins with similar antitumor properties were also isolated from this bacterium and these cytotoxic proteins with specific activity against human cancer cells were named parasporins. At present, nineteen different parasporins are registered and classified in six families. These parasporins have been described to have specific in vitro antitumor activity against several cancer cell lines. The antitumor activity makes parasporins possible candidates as anticancer agents. Various research groups around the world are involved in isolating and characterizing in vitro antitumor activity of these proteins and many articles reporting such activities in detail have been published. However, there are virtually no data regarding the antitumor activity of parasporins in vivo. This review summarizes the properties of these potentially useful antitumor agents of natural origin, focusing on their in vivo activity thus also highlighting the importance of testing these proteins in animal models for a possible application in clinical oncology.