{"doi":"10.1016/j.omto.2022.05.005","title":"Advancing together and moving forward: Combination gene and cellular immunotherapies","abstract":"Over the past decade, we have witnessed the successful translation of cancer therapies that have aimed to rewire the immune system to target a wide array of tumor types. These immunotherapies are composed of distinct modalities that include the release of immunological breaks by immune checkpoint blockade to boost endogenous anti-tumor responses, bispecific antibodies that redirect specificity of endogenous T cells to target tumor cells, adoptive transfer of engineered cell therapies that redirect cytolytic activity of T cells and other immune effector cells to target tumors, and therapeutic oncolytic viruses that are selective in infection, replication, and lysis of tumor cells (Figure 1). To date, each of these modalities have been approved by the U.S. Food and Drug Administration (FDA), starting with the approval of the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody, ipilimumab, in 2011 for treating patients with melanoma. Since then, eight additional immune oncological (IO) agents that target programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have been approved by the FDA, including the newest agent that targets lymphocyte activation gene 3 (LAG-3), which was approved earlier this year. Additional immune checkpoints are being discovered, and hundreds of clinical trials are ongoing that are evaluating single and combination immune checkpoint-blocking drugs for treating patients with cancer and other disease indications. The first bispecific, called blinatumomab, which targets cluster of differentiation 19 (CD19) for treating patients with B-cell leukemia, was approved by the FDA in 2015. Since then, two additional bispecifics have been FDA-approved for treating patients with non-small cell lung cancer and patients with hemophilia, with numerous bispecifics in late-stage clinical development for treating patients with other tumor types. Beyond targeting immune checkpoint pathways, chimeric antigen receptor (CAR)-based T cell therapies have been successful since 2017, including the first FDA-approved CAR T cell that targets CD19, called axicabtagene ciloleucel, for treating patients with relapsed refractory B cell lymphoma. This was followed by four additional FDA approvals of CD19-CAR T cells that target other B cell malignancies, including the approval of two B cell maturation antigen-redirected CAR T cells within the last 2 years for treating patients with multiple myeloma. Oncolytic viruses, which have been investigated for many decades, received the first and only FDA approval in 2015 for a genetically modified herpes simplex virus, talimogene laherparepvec, for treating patients with melanoma, with a variety of viral strains being evaluated as potential cancer treatments. A new chapter in translational immunotherapy is evolving based on the combined knowledge of tumor immunology and better understanding of an IO agent’s safety and efficacy. Through a collection of original research articles and reviews, this special issue of Molecular Therapy – Oncolytics presents many of the challenges and promises of cellular- and viral-based combination immunotherapies. Adoptive CAR T cell therapy can conquer the stream of challenges that comes with treating hematological malignancies by combining advances in genetic engineering and T cell manufacturing. The next step, after successfully crossing the river of liquid tumors, is to overcome the uphill battle of treating solid tumors. While advances in cellular engineering can be deployed to treat solid tumors, they clearly need to be optimized to be effective in the solid tumor microenvironment. The major challenges facing CAR T cell immunotherapies that target solid tumors are the lack of uniform and tumor-restricted antigen targets, and the ineffective trafficking, survival, and function of adoptively transferred cells in the immunosuppressive solid tumor microenvironment.1Morello A. Sadelain M. Adusumilli P.S. Mesothelin-targeted CA","journal":"Molecular Therapy — Oncolytics","year":2022,"id":294234,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":615635,"name":"Waseem Cheema","orcid":"0000-0002-8000-7493","position":1,"is_corresponding":false},{"id":227919,"name":"Prasad S. Adusumilli","orcid":"0000-0002-1699-2046","position":2,"is_corresponding":false},{"id":457033,"name":"Saul J. Priceman","orcid":"0000-0002-8136-2112","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:30:57.469517Z","pmid":"35694448","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}