For the monitoring of chimeric antigen receptor (CAR) T-cell therapies, antigen-based CAR detection methods are usually applied. However, for each target-antigen, a separate detection system is required. Furthermore, when monitored CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods produce false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment promise a universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19-targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel, the sensitivity was significantly lower compared to that for antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel, or Ide-cel, respectively. Cilta-cel (containing a monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but are not universally applicable.

OBJECTIVE: Valuing and pricing the components of combination therapies can be difficult because of competition law issues, difficulty implementing different prices for the same product in alternative uses, and attributing value to each component of the combination. We propose a value attribution solution that allows all combination components to be priced according to their relative value in the combination.
METHODS: We developed a value attribution solution that is universal, symmetrical, and neutral to each combination constituent, regardless of whether it is the backbone or the add-on, and complete, meaning that it will always attribute the full value of the combination between the component parts. Moreover, it can be applied to any number of components in the combination (eg, triplets or quadruplets). We compared this solution with 2 other existing approaches.
RESULTS: The results of the proposed value attribution solution sit between those of the 2 other value attribution approaches as it combines elements of each. As the degree of additivity moves further away from one in either direction, then our general approach ratios also move, reflecting the impact of the incremental value.
CONCLUSIONS: The proposed value attribution solution for combination therapies differs from 2 existing approaches by being universally applicable and allowing for symmetry when neutral to the constituent components of the combination. To optimally contribute to policy debate and practice, various requirements for its implementation need to be well understood, including how to overcome (1) partial information, (2) whether its assumptions can be relaxed, and (3) implementation issues.

In preclinical tumor models, cyclic fasting and fasting-mimicking diets (FMDs) produce antitumor effects that become synergistic when combined with a wide range of standard anticancer treatments while protecting normal tissues from treatment-induced adverse events. More recently, results of phase 1/2 clinical trials showed that cyclic FMD is safe, feasible, and associated with positive metabolic and immunomodulatory effects in patients with different tumor types, thus paving the way for larger clinical trials to investigate FMD anticancer activity in different clinical contexts. Here, we review the tumor-cell-autonomous and immune-system-mediated mechanisms of fasting/FMD antitumor effects, and we critically discuss new metabolic interventions that could synergize with nutrient starvation to boost its anticancer activity and prevent or reverse tumor resistance while minimizing toxicity to patients. Finally, we highlight potential future applications of FMD approaches in combination with standard anticancer strategies as well as strategies to implement the design and conduction of clinical trials.

A growing body of literature reports on the combined use of peptide receptor radionuclide therapy (PRRT) with other anti-tumuor therapies in order to anticipate synergistic effects with perhaps increased safety issues. Combination treatments to enhance PRRT outcome are based on improved tumour perfusion, upregulation of somatostatin receptors (SSTR), radiosensitization with DNA damaging agents or targeted therapies. Several Phase 1 or 2 trials are currently recruiting patients in combined regimens. The combination of PRRT with cytotoxic chemotherapy, capecitabine and temozolomide (CAPTEM), seems to become clinically useful especially in pancreatic neuroendocrine tumours (pNETs) with acceptable safety profile. Neoadjuvant PRRT prior to surgery, PRRT combinations of intravenous and intraarterial routes of application, combinations of PRRT with differently radiolabelled (alpha, beta, Auger) SSTR-targeting agonists and antagonists, inhibitors of immune checkpoints (ICIs), poly (ADP-ribose) polymerase-1 (PARP1i), tyrosine kinase (TKI), DNA-dependent protein kinase, ribonucleotide reductase or DNA methyltransferase (DMNT) are tested in currently ongoing clinical trials. The combination with [131I]I-MIBG in rare NETs (such as paraganglioma, pheochromocytoma) and new non-SSTR-targeting radioligands are used in the personalization process of treatment. The present review will provide an overview of the current status of ongoing PRRT combination treatments.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Currently, standard treatment options for TNBC are limited to surgery, adjuvant chemotherapy, and radiotherapy. However, these treatment methods are associated with a higher risk of intrinsic or acquired recurrence. Antibody-drug conjugates (ADCs) have emerged as a useful and promising class of cancer therapeutics. ADCs, also known as \"biochemical missiles\", use a monoclonal antibody (mAb) to target tumor antigens and deliver a cytotoxic drug payload. Currently, several ADCs clinical studies are underway worldwide, including sacituzumab govitecan (SG), which was recently approved by the FDA for the treatment of TNBC. However, due to the fact that only a small portion of TNBC patients respond to ADC therapy and often develop resistance, growing evidence supports the use of ADCs in combination with other treatment strategies to treat TNBC. In this review, we described the current utilization of ADCs and discussed the prospects of ADC combination therapy for TNBC.

The increase in cancer diagnoses and cancer deaths, severe side effects of existing treatments and resistance to traditional treatments have generated a need for new anticancer treatments. Glioblastoma multiforme (GBM) is the most common, malignant and aggressive brain cancer. Despite many innovations regarding GBM treatment, the final outcome is still very poor, making it necessary to develop new therapeutic approaches. Cold atmospheric plasma (CAP) as well as plasma-activated liquids (PAL) are being studied as new possible approaches against cancer. The anticancer activity of PAL such as \"plasma-activated water\" (PAW) is dependent on the reactive chemical compounds present in the solution. Possible combinatory effects with conventional therapies, such as chemotherapeutics, may expand the potential of PAL for cancer treatment. We aim to explore the therapeutic properties of a combination of PAW and topotecan (TPT), an antineoplastic agent with major cytotoxic effects during the S phase of the cell cycle, on a GBM cancer cell line (U-251mg). Combined treatments with PAW and TPT showed a reduction in the metabolic activity and cell mass, an increase in apoptotic cell death and a reduction in the long-term survival. Single applications of PAW+TPT treatments showed a cytotoxic effect in the short term and an antiproliferative effect in the long term, warranting future exploration of combining PAW with chemotherapeutic agents as new therapeutic approaches.

Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. The most recurrent event in UM is the activation of Gαq signaling induced by mutations in GNAQ/11. These mutations activate downstream effectors including protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Clinical trials with inhibitors of these targets have not demonstrated a survival benefit for patients with UM metastasis. Recently, it has been shown that GNAQ promotes YAP activation through the focal adhesion kinase (FAK). Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM both in vitro and in vivo. In this study, we have evaluated the synergy of the FAK inhibitor with a series of inhibitors targeting recognized UM deregulated pathways in a panel of cell lines. The combined inhibition of FAK and MEK or PKC had highly synergistic effects by reducing cell viability and inducing apoptosis. Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM.

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Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients\' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients.

BACKGROUND: Novel oncology treatment strategies increasingly use medicines with distinct but complementary mechanisms of action in combination or in close sequence. Payers, when confronted with higher total cost of providing combination regimens involving multiple therapies and usually longer treatment durations, are reluctant to reimburse them, particularly when they perceive the expected incremental benefits from adding a new medicine (the add-on) to a currently reimbursed medicine (the backbone) not to represent value for money to the health system. Nevertheless, depending on how value is attributed to the add-on versus the backbone, a clinically effective medicine used as part of a regimen that increases treatment duration might be found \"not cost-effective at zero price.\" This phenomenon, signaling a policy problem not a pricing issue, first needs to be better understood before a generalizable and transparent solution can be presented.
OBJECTIVE: This article sets out when this policy challenge arises and describes general principles that any proposed solution to the value attribution problem must satisfy.
METHODS: We develop a simplified conceptual framework and use this to address 2 topics. The first is to understand the origin of problems posed by the current approach for attributing value in incremental cost-effectiveness analyses of combination regimens. The second is to discuss 2 new approaches in the literature designed to address the challenge.
RESULTS: We find that neither meets our criteria, meaning that further work is needed to resolve the issue. Finally, we briefly discuss the implications of relaxing the simplifying assumptions in our conceptual framework.