Review

Authors: Feroza Yasinjan, Yang Xing, Huayue Geng...

Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of relentless pursuit in exploring novel therapeutic approaches for GBM, there is limited progress in improving patients' survival outcomes. Numerous obstacles impede the effective treatment of GBM, including the immunosuppressive tumor microenvironment (TME), the blood-brain barrier, and extensive heterogeneity. Despite these challenges, immunotherapies are emerging as a promising avenue that may offer new hope for the treatment of gliomas. There are four main types of immunotherapies for gliomas, immune checkpoint blockades, chimeric antigen receptor T-cell therapies, vaccines, and oncolytic viruses. In addition, gene therapy, bispecific antibody therapy, and combine therapy are also briefly introduced in this review. The significant role of TME in the process of immunotherapies has been emphasized in many studies. Although immunotherapy is a promising treatment for gliomas, enormous effort is required to overcome the existing barriers to its success. Owing to the rapid development and increasing attention paid to immunotherapies for gliomas, this article aims to review the recent advances in immunotherapies for gliomas.

Topics: Humans; Immunotherapy; Glioma; Glioblastoma; Immunotherapy, Adoptive; Radioimmunotherapy; Tumor Microenvironment

PubMed: 37744349
DOI: 10.3389/fimmu.2023.1255611

Review

Authors: Luiz Henrique de Assis, Daniel El Fassi, Martin Hutchings...

Management of hematological malignancies is rapidly evolving from chemotherapy-based regimens toward targeted agents and immunotherapies, including bispecific antibodies (BsAbs). These novel and highly active treatments come with new side effect profiles. The hematological toxicities are common and potentially harmful, and the side effects have hitherto not been reviewed. With many BsAbs recently approved and entering routine clinical use, we have reviewed the rather limited published data and propose recommendations on the management of these toxicities. Our review of the available data confirms that hematological toxicities are among the most common toxicities, with potentially harmful consequences for the patients. Fortunately, hemophagocytic lymphohystiocytosis and disseminated intravascular coagulation are rare. Severe neutropenia and hypogammaglobulinemia are manageable, and their timely treatment and prevention may reduce morbidity and mortality.

Topics: Humans; Antibodies, Bispecific; Radioimmunotherapy; Hematologic Neoplasms; Immunotherapy

PubMed: 38066890
DOI: 10.1182/hematology.2023000508

Review

Authors: Jingyi Shi, Zhuang Sun, Zhaoya Gao...

Colorectal cancer (CRC) is a deadly form of cancer worldwide. Patients with locally advanced rectal cancer and metastatic CRC have a poor long-term prognosis, and rational and effective treatment remains a major challenge. Common treatments include multi-modal combinations of surgery, radiotherapy, and chemotherapy; however, recurrence and metastasis rates remain high. The combination of radiotherapy and immunotherapy (radioimmunotherapy [RIT]) may offer new solutions to this problem, but its prospects remain uncertain. This review aimed to summarize the current applications of radiotherapy and immunotherapy, elaborate on the underlying mechanisms, and systematically review the preliminary results of RIT-related clinical trials for CRC. Studies have identified several key predictors of RIT efficacy. Summarily, rational RIT regimens can improve the outcomes of some patients with CRC, but current study designs have limitations. Further studies on RIT should focus on including larger sample sizes and optimizing the combination therapy regimen based on underlying influencing factors.

Topics: Humans; Radioimmunotherapy; Combined Modality Therapy; Immunotherapy; Treatment Outcome; Colorectal Neoplasms

PubMed: 37234164
DOI: 10.3389/fimmu.2023.1105180

Review

Authors: Poul F Høilund-Carlsen, Abass Alavi, Rudolph J Castellani...

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.

Topics: United States; Humans; Alzheimer Disease; Ice Cover; Amyloidogenic Proteins; Radioimmunotherapy; Antibodies, Monoclonal, Humanized

PubMed: 38612701
DOI: 10.3390/ijms25073892

Review

Authors: Ainhoa Arina, Stanley I Gutiontov, Ralph R Weichselbaum...

In the era of cancer immunotherapy, there is significant interest in combining conventional cancer therapies, such as radiotherapy, with drugs that stimulate the immune system. The observation that ionizing radiation applied to murine tumors delays the growth of distant tumors ("abscopal effect") and that this effect is potentiated by immunostimulatory drugs, led to clinical trials in which often only one lesion is irradiated in combination with immunotherapy drugs. The results of these initial clinical trials combining radio therapy and immunotherapy show that a meaningful abscopal effect is still infrequent. Recent preclinical data suggest that preexistent intratumoral T cells can survive radiation and contribute to its therapeutic effect. In this review, we discuss possible mechanisms underlying the preclinical/clinical discrepancies regarding the abscopal effect, and we propose the irradiation of multiple or all tumor sites in combination with systemic immunotherapy as a possible avenue to increase the efficacy of radio-immunotherapy.

Topics: Animals; Humans; Immunotherapy; Neoplasms; Radioimmunotherapy; Radiotherapy

PubMed: 32047000
DOI: 10.1158/1078-0432.CCR-19-2034

Authors: Xiaolin Shi, Yiwei Yang, Wei Zhang...

DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8 T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8 T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.

Topics: Mice; Animals; Radioimmunotherapy; X-Rays; Pyroptosis; Immune Checkpoint Inhibitors; Ligands; Nucleotidyltransferases; Neoplasms

PubMed: 36256824
DOI: 10.1073/pnas.2208506119

Authors: Brian H Santich, Sarah M Cheal, Mahiuddin Ahmed...

PURPOSE

Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index.

EXPERIMENTAL DESIGN

The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses.

RESULTS

SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (Ac, 1.48 MBq/kg) or beta-emitting (Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver.

CONCLUSIONS

The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose..

Topics: Animals; Humans; Mice; Mice, Nude; Molecular Targeted Therapy; Neoplasms; Positron Emission Tomography Computed Tomography; Radioimmunotherapy; Xenograft Model Antitumor Assays

PubMed: 32958698
DOI: 10.1158/1078-0432.CCR-20-2150

Review

Authors: Konstantin Dobrenkov, Nai-Kong V Cheung

Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions.

Topics: Adult; Animals; Antibodies, Monoclonal; Gangliosides; Humans; Immunotherapy; Neoplasms; Protein Engineering; Radioimmunotherapy

PubMed: 25440605
DOI: 10.1053/j.seminoncol.2014.07.003

Authors: Andreas K Buck, Sebastian E Serfling, Sabrina Kraus...

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Topics: Humans; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Precision Medicine; Positron Emission Tomography Computed Tomography; Lymphoma, B-Cell; Radioimmunotherapy; Yttrium Radioisotopes

PubMed: 37290799
DOI: 10.2967/jnumed.122.265199

Authors: Markus Hecht, Markus Eckstein, Sandra Rutzner...

PURPOSE

The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed.

METHODS

Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%.

RESULTS

Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%).

CONCLUSIONS

The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS.

TRIAL REGISTRATION NUMBER

The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Female; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Induction Chemotherapy; Male; Middle Aged; Patient Selection; Radioimmunotherapy; Squamous Cell Carcinoma of Head and Neck

PubMed: 35078923
DOI: 10.1136/jitc-2021-003747