While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.

Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P‐gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Co‐administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (C_max) and area under the plasma concentration‐time curve from time zero to the last quantifiable concentration (AUC_(0‐tlast)) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 143% (112, 183) and 120% (97, 148), respectively. Co‐administration with tacrolimus resulted in reduction in apixaban C_max and AUC_(0‐tlast) with associated GMRs (90% CI) of 87% (69, 112) and 78% (63, 97), respectively. The observed changes in apixaban exposure margins with cyclosporine or tacrolimus are within the range of the historical clinical development program, therefore, apixaban dose adjustments are not warranted.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, ‘on-target, off-tumor’ immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.

Background: Outpatient chemotherapy often leaves patients to grapple with a range of complex side effects at home. Leveraging tailored evidence-based content to monitor and manage these symptoms remains an untapped potential among patients with gastrointestinal (GI) cancer. Objective: This study aims to bridge the gap in outpatient chemotherapy care by integrating a cutting-edge text messaging system with a chatbot interface. This approach seeks to enable real-time monitoring and proactive management of side effects in patients with GI cancer undergoing intravenous chemotherapy. Methods: Real-Time Chemotherapy-Associated Side Effects Monitoring Supportive System (RT-CAMSS) was developed iteratively, incorporating patient-centered inputs and evidence-based information. It synthesizes chemotherapy knowledge, self-care symptom management skills, emotional support, and healthy lifestyle recommendations. In a single-arm 2-month pilot study, patients with GI cancer undergoing chemotherapy received tailored intervention messages thrice a week and a weekly Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events–based symptom assessment via a chatbot interface. Baseline and postintervention patient surveys and interviews were conducted. Results: Out of 45 eligible patients, 34 were enrolled (76% consent rate). The mean age was 61 (SD 12) years, with 19 (56%) being females and 21 (62%) non-Hispanic White. The most common cancer type was pancreatic (n=18, 53%), followed by colon (n=12, 35%) and stomach (n=4, 12%). In total, 27 (79% retention rate) participants completed the postintervention follow-up. In total, 20 patients texted back at least once to seek additional information, with the keyword “chemo” or “support” texted the most. Among those who used the chatbot system checker, fatigue emerged as the most frequently reported symptom (n=15), followed by neuropathy (n=7). Adjusted for multiple comparisons, patients engaging with the platform exhibited significantly improved Patient Activation Measure (3.70, 95% CI –6.919 to –0.499; P=.02). Postintervention interviews and satisfaction surveys revealed that participants found the intervention was user-friendly and were provided with valuable information. Conclusions: Capitalizing on mobile technology communication holds tremendous scalability for enhancing health care services. This study presents initial evidence of the engagement and acceptability of RT-CAMSS, warranting further evaluation in a controlled clinical trial setting.

PURPOSE: BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis. MATERIALS AND METHODS: The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE. RESULTS: Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m ² once every week to 10.0 mg/m ² once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m ² once every 2 weeks was selected as a RP2D. At 6.5 mg/m ² once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours). CONCLUSION: BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m ² once every 2 weeks.

Introduction: There is a high incidence of venous thromboembolism (VTE) in solid organ transplant recipients. The safety and efficacy of direct-acting oral anticoagulants (DOAC) have been well established in clinical practice for the prevention and treatment of VTE in broad populations. However, the management of VTE in the setting of solid organ transplantation remains a challenge to clinicians due to limited evidence of DOAC usage with calcineurin inhibitors. Areas covered: The current literature available on the pharmacokinetic–pharmacodynamic interaction between DOACs and calcineurin inhibitors is presented. A comprehensive review was undertaken using PubMed, Embase, drug product labeling, and drug product review conducted by the US Food and Drug Administration using Drugs@FDA. The potential for mitigation strategies and clinical management using extant knowledge is explored. Expert opinion: Immunosuppression therapy is necessary to prevent graft rejection by the host. The sparsity of data together with the lack of well-designed prospective studies of DOAC use in solid organ transplant recipients presents a unique challenge to clinicians in determining the clinical relevance of possible drug interactions. Existing evidence suggests that with attention to concomitant drug use and renal function, the co-administration of DOACs and calcineurin inhibitors is safe and effective.