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Expert Opinion on Biological Therapy May 2022Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a highly personalized type of cancer immunotherapy. TIL-based ACT exploits naturally occurring... (Review)
Review
INTRODUCTION
Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a highly personalized type of cancer immunotherapy. TIL-based ACT exploits naturally occurring TILs, derived from the patients' tumor. This treatment has shown consistent clinical responses in melanoma, and recent results point toward a potential use in multiple cancer diagnoses. However, several limitations have restricted the clinical development and adaptation of TIL-based ACT.
AREAS COVERED
In this review, we present the principles of TIL-based ACT and discuss the most significant limitations for therapeutic efficacy and its widespread application. The topics of therapeutic resistance (both innate and acquired), treatment-related toxicity, and the novel research topic of metabolic barriers in the tumor microenvironment (TME) are covered.
EXPERT OPINION
There are many ongoing areas of research focusing on improving clinical efficacy and optimizing TIL-based ACT. Many strategies have shown a great potential, particularly strategies advancing TIL efficacy (such as increasing and harnessing the sub-population of tumor-reactive TILs) and manufacturing processes. Novel approaches can help overcome current limitations and potentially result in TIL-based ACT entering the mainstream of cancer therapy across tumor types.
Topics: Cell- and Tissue-Based Therapy; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Melanoma; Tumor Microenvironment
PubMed: 35414331
DOI: 10.1080/14712598.2022.2064711 -
Nature Reviews. Clinical Oncology Apr 2023Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing... (Review)
Review
Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing CAR designs and cell products, improving response rates, extending the durability of remissions, reducing toxicity and broadening the utility of this therapeutic modality to other cancer types. Data from multidimensional omics analyses, including genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and/or microbiomics, provide unique opportunities to dissect the complex and dynamic multifactorial phenotypes, processes and responses of CAR T cells as well as to discover novel tumour targets and pathways of resistance. In this Review, we summarize the multidimensional cellular and molecular profiling technologies that have been used to advance our mechanistic understanding of CAR T cell therapies. In addition, we discuss current applications and potential strategies leveraging multi-omics data to identify optimal target antigens and other molecular features that could be exploited to enhance the antitumour activity and minimize the toxicity of CAR T cell therapy. Indeed, fully utilizing multi-omics data will provide new insights into the biology of CAR T cell therapy, further accelerate the development of products with improved efficacy and safety profiles, and enable clinicians to better predict and monitor patient responses.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Genomics; Proteomics; Hematologic Neoplasms
PubMed: 36721024
DOI: 10.1038/s41571-023-00729-2 -
European Journal of Haematology Dec 2022Hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, particularly considering patients who manifest multiple... (Review)
Review
Hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, particularly considering patients who manifest multiple refractory diseases. Recently, chimeric antigen receptor (CAR)-T cell therapy has emerged as a potential treatment option for relapsed/refractory B cell malignancies, which have motivated the Food and Drug Administration approval of a series of products based on this technique. The objective of this systematic review was to assess the efficacy and safety of CAR-T cell therapy for patients with hematological malignancies. A comprehensive literature search was conducted in the electronic databases (CENTRAL, Embase, LILACS, and MEDLINE), clinical trials register platforms (Clinicaltrials.gov and WHO-ICTRP), and grey literature (OpenGrey). The Cochrane Handbook for Reviews of Interventions was used for developing the review and the PRISMA Statement for manuscript reporting. The protocol was prospectively published in PROSPERO database (CRD42020181047). After the selection process, seven RCTs were included, three of which with available outcome results. The available results are from studies assessing axicabtagene, lisocabtagene, and tisagenlecleucel for patients with B cell lymphoma, and the certainty of evidence ranged from very low to low for survival and progression-related outcome and for safety outcomes. Additionally, four randomized controlled trials comparing CAR-T cell therapy to the standard treatment for various types of relapsed/refractory B cell non-Hodgkin lymphomas and multiple myeloma included in this systematic review still did not have available outcome data. The results of this review may be used to guide clinical practice but evidence concerning the safety and efficacy of CAR-T Cell therapy for hematological malignancies is still immature to recommend its application outside of clinical trials or compassionate use context for advanced and terminal cases. It is expected the results of the referred comparative studies will provide further elements to subsidize the broader application of this immunotherapy.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Hematologic Neoplasms; Lymphoma, B-Cell; Cell- and Tissue-Based Therapy
PubMed: 36018500
DOI: 10.1111/ejh.13851 -
Journal of Hematology & Oncology Nov 2022Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK... (Review)
Review
Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.
Topics: Humans; Killer Cells, Natural; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Neoplasms; Hematologic Neoplasms
PubMed: 36348457
DOI: 10.1186/s13045-022-01382-5 -
The Journal of Allergy and Clinical... Feb 2022Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for aggressive relapsed/refractory hematologic malignancies. However, side effects including severe infections can be life-threatening. Multiple factors, including cytokine release syndrome, B-cell aplasia, and hypogammaglobulinemia, contribute to infection risk. B-cell aplasia is an expected on-target, off-tumor effect of CD19-targeted CAR T cells and leads to hypogammaglobulinemia. We review hypogammaglobulinemia observed in the 5 currently Food and Drug Administration-approved CAR T-cell therapies and other CAR T-cell products evaluated in clinical trials, and discuss hypogammaglobulinemia onset, duration, and immune recovery. We review associations between hypogammaglobulinemia and infections, with a discussion informed by other known B-cell-depleting contexts. Differences in hypogammaglobulinemia between children and adults are identified. We integrate management strategies for evaluation and immunoglobulin replacement from clinical studies, expert recommendations, and organizational guidelines. Notably, our review also highlights newer CAR T-cell products targeting different B-cell antigens, including B-cell maturation antigen, signaling lymphocytic activation molecule, and κ light chains. Finally, we identify key areas for future study to mitigate and treat hypogammaglobulinemia resulting from this transformative therapy.
Topics: Agammaglobulinemia; Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 34757064
DOI: 10.1016/j.jaip.2021.10.037 -
Frontiers in Immunology 2023Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain... (Review)
Review
Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain hematologic malignancies. However, there are several limitations that need to be addressed to target more cancer types. Natural killer (NK) cells are a type of innate immune cells that represent a unique biology in cancer immune surveillance. In particular, NK cells obtained from heathy donors can serve as a source for genetically engineered immune cell therapies. Therefore, NK-based therapies, including NK cells, CAR-NK cells, and antibodies that induce antibody-dependent cellular cytotoxicity of NK cells, have emerged. With recent advances in genetic engineering and cell biology techniques, NK cell-based therapies have become promising approaches for a wide range of cancers, viral infections, and senescence. This review provides a brief overview of NK cell characteristics and summarizes diseases that could benefit from NK-based therapies. In addition, we discuss recent preclinical and clinical investigations on the use of adoptive NK cell transfer and agents that can modulate NK cell activity.
Topics: Humans; Killer Cells, Natural; Immunotherapy, Adoptive; Neoplasms; Immunotherapy; Genetic Therapy
PubMed: 37539051
DOI: 10.3389/fimmu.2023.1192907 -
Nature Medicine Sep 2022Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and...
Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4Helios CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (T) cells. Validation cohort analysis upheld the link between higher CAR T cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR T cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.
Topics: Antigens, CD19; Humans; Immunotherapy, Adoptive; Lactate Dehydrogenases; Neurotoxicity Syndromes; Proteomics; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 36097223
DOI: 10.1038/s41591-022-01960-7 -
Journal of Clinical Oncology : Official... Feb 2020The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r)... (Clinical Trial)
Clinical Trial
PURPOSE
The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy.
METHODS
Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity.
RESULTS
Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%).
CONCLUSION
Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
Topics: Adult; Age Factors; Aged; Female; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Survival Rate; Young Adult
PubMed: 31815579
DOI: 10.1200/JCO.19.01892 -
Blood Mar 2022Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small...
Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
Topics: Antigens, CD19; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Recurrence
PubMed: 34699592
DOI: 10.1182/blood.2021011895 -
Nature Medicine Jul 2023In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising...
In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.
Topics: Humans; Adult; Immunotherapy, Adoptive; Interleukin 1 Receptor Antagonist Protein; Neurotoxicity Syndromes; Lymphoma, Large B-Cell, Diffuse; Antigens, CD19
PubMed: 37400640
DOI: 10.1038/s41591-023-02404-6