Neoadjuvant therapy in MIBC
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A conditionally replicative adenovirus vector containing the synNotch receptor gene for the treatment of muscle-invasive bladder cancer
Muscle-invasive bladder cancer (MIBC), a highly heterogeneous disease, shows genomic instability and a high mutation rate, making it difficult to treat. Recent studies revealed that cancer stem cells (CSCs) play a critical role in MIBC frequent recurrence and high morbidity. Previous research has shown that Cyclooxygenases-2 (COX-2) is particularly highly expressed in bladder cancer cells. In recent years, the development of oncolytic adenoviruses and their use in clinical trials have gained increased attention. In this study, we composed a conditionally replicative adenovirus vector (CRAd-synNotch) that carries the COX-2 promotor driving adenoviral E1 gene, the synNotch receptor therapeutic gene, and the Ad5/35 fiber gene. Activation of the COX-2 promoter gene causes replication only within COX-2 expressing cancer cells, thereby leading to tumor oncolysis. Also, CD44 and HIF signals contribute to cancer stemness and maintaining CSCs in bladder cancer, and the transduced synNotch receptor inhibits both CD44 and HIF signals simultaneously. We performed an in vivo study using a mouse xenograft model of T24 human MIBC cells and confirmed the significant antitumor activity of CRAd-synNotch. Our findings in this study warrant the further development of CRAd-synNotch for treating patients with MIBC.
Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma
Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH–wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927).
The guided fire from within: intratumoral administration of mRNA-based vaccines to mobilize memory immunity and direct immune responses against pathogen to target solid tumors
We investigated a novel cancer immunotherapy strategy that effectively suppresses tumor growth in multiple solid tumor models and significantly extends the lifespan of tumor-bearing mice by introducing pathogen antigens into tumors via mRNA-lipid nanoparticles. The pre-existing immunity against the pathogen antigen can significantly enhance the efficacy of this approach. In mice previously immunized with BNT162b2, an mRNA-based COVID-19 vaccine encoding the spike protein of the SARS-CoV-2 virus, intratumoral injections of the same vaccine efficiently tagged the tumor cells with mRNA-expressed spike protein. This action rapidly mobilized the pre-existing memory immunity against SARS-CoV-2 to kill the cancer cells displaying the spike protein, while concurrently reprogramming the tumor microenvironment (TME) by attracting immune cells. The partial elimination of tumor cells in a normalized TME further triggered extensive tumor antigen-specific T cell responses through antigen spreading, eventually resulting in potent and systemic tumor-targeting immune responses. Moreover, combining BNT162b2 treatment with anti-PD-L1 therapy yielded a more substantial therapeutic impact, even in “cold tumor” types that are typically less responsive to treatment. Given that the majority of the global population has acquired memory immunity against various pathogens through infection or vaccination, we believe that, in addition to utilizing the widely held immune memory against SARS-CoV-2 via COVID-19 vaccine, mRNA vaccines against other pathogens, such as Hepatitis B Virus (HBV), Common Human Coronaviruses (HCoVs), and the influenza virus, could be rapidly transitioned into clinical use and holds great promise in treating different types of cancer. The extensive selection of pathogen antigens expands therapeutic opportunities and may also overcome potential drug resistance.
International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma
T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.
Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial)
We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Secondary end points included safety, relapse-free survival and overall survival, time to occurrence of new basal cell carcinomas and biological read outs. Only mild adverse events occurred. The 6-month relapse-free survival and overall survival rates were 100%. In two patients a new basal cell carcinoma was diagnosed. T-VEC led to a significant increase in cytotoxic T cells (P = 0.0092), B cells (P = 0.0004) and myeloid cells (P = 0.0042) and a decrease in regulatory T cells (P = 0.0290) within the tumor microenvironment. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect basal cell carcinomas (EudraCT no. 2018-002165-19).
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