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Nature Medicine Jan 2023Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted...
Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.
Topics: Male; Humans; Antigens, Neoplasm; Neoplasm Proteins; Head and Neck Neoplasms; HLA-A Antigens; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive
PubMed: 36624315
DOI: 10.1038/s41591-022-02128-z -
CA: a Cancer Journal For Clinicians Jan 2022Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies.... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.
Topics: Critical Care; Cytokine Release Syndrome; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Neurotoxicity Syndromes; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 34613616
DOI: 10.3322/caac.21702 -
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 -
Blood Jul 2022Derivation of CD7-targeted chimeric antigen receptor (7CAR) T cells often requires genetic manipulations to ablate the CD7 gene or block CD7 cell surface expression. Our...
Derivation of CD7-targeted chimeric antigen receptor (7CAR) T cells often requires genetic manipulations to ablate the CD7 gene or block CD7 cell surface expression. Our novel approach deriving naturally selected 7CAR (NS7CAR) T cells from bulk T cells was able to overcome major fratricide by minimizing accessible CD7 epitopes. The CD7 molecules of NS7CAR T cells were masked or sequestered by the CD7-targeting CAR. Compared with sorted CD7-negative 7CAR T cells and CD7 knocked-out 7CAR T cells, NS7CAR exhibited similar or superior therapeutic properties, including a greater percentage of CAR+ cells and a higher proportion of CD8+ central memory T cells. In our first-in-human phase 1 trial (NCT04572308), 20 patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) (n = 14) and T-cell lymphoblastic lymphoma (T-LBL) (n = 6) were treated with NS7CAR. Nineteen patients achieved minimal residual disease negative complete remission (CR) in the bone marrow (BM) by day 28, and 5 of 9 patients achieved extramedullary CR. With a median follow-up of 142.5 (32-311) days after infusion, 14 patients subsequently received allogeneic hematopoietic stem cell transplant (10 consolidative, 4 salvage) following NS7CAR infusion with no relapses to date. Of the 6 patients who did not receive a transplant, 4 remained in CR at a median time of 54 (32-180) days. Eighteen patients experienced mild cytokine release syndrome (CRS) (grade ≤2), 1 developed grade 3 CRS, and 2 had grade 1 neurotoxicity. These results indicate that NS7CAR-T therapy is a safe and highly effective treatment for T-ALL/LBL. More patients and longer follow-up are needed for validation.
Topics: Antigens, CD19; Humans; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35500125
DOI: 10.1182/blood.2021014498 -
Cancer Immunology, Immunotherapy : CII Feb 2023Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although αβ T cells are time-tested chassis for CAR,... (Review)
Review
Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although αβ T cells are time-tested chassis for CAR, potential graft versus host disease (GvHD) apart from cytokine toxicity and antigen escape pose limitations to this approach. αβ T cell malignancy challenges isolation and expansion of therapeutic T cells. Moreover, αβ T cells may pose toxicity risk to inflammation sensitive vital tissues bearing the tumor. The HLA independent, multivalent, versatile and systemic anti-tumor immunity increases the desirability of γδ T cells as an alternate chassis for CAR. Indeed, CD19 γδ CAR T cell therapy to treat advanced lymphoma reached a milestone with the fast track status by FDA. However, reduced tumor-toxicity, homing, in vivo persistence and heterogeneity limits the translation of this therapy. The field is gaining momentum in recent years with optimization of gene delivery approaches and mechanistic insights into co-signaling requirements in γδ T cells. There is a renewed interest in customizing design of CAR guided by the biology of the host immune cells. Progress has been made in the current good manufacturing practice compatible expansion and engineering protocols for the δ1 and δ2 T cells. γδ CAR T cells may find its niche in the clinical situations wherein conventional CAR therapy is less suitable due to propensity for cytokine toxicity or off-tumor effect. As the therapy is moving towards clinical trials, this review chronicles the hitherto progress in the therapeutic engineering of γδ T cells for cancer immunotherapy.
Topics: Humans; T-Lymphocytes; Neoplasms; Immunotherapy, Adoptive; Lymphoma; Cytokines; Immunotherapy
PubMed: 35960333
DOI: 10.1007/s00262-022-03260-y -
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 -
Technology in Cancer Research &... 2023Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and... (Review)
Review
Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and non-specific) into patients to kill tumor cells either directly or indirectly by stimulating the body's immune system. The patient's (autologous) or a donor's (allogeneic) immune cells are used to improve immune function. Chimeric antigen receptor (CAR) T cells (CAR-T) is a type of ACT that has gained attention. T cells from the peripheral blood are genetically engineered to express CARs that rapidly proliferate and specifically recognize target antigens to exert its anti-tumor effects. Clinical application of CAR-T therapy for hematological tumors has shown good results, but adverse reactions and recurrence limit its applicability. Tumor infiltrating lymphocyte (TIL) therapy is effective for solid tumors. TIL therapy exhibits T cell receptor (TCR) clonality, superior tumor homing ability, and low targeted toxicity, but its successful application is limited to a number of tumors. Regardless, TIL and CAR-T therapies are effective for treating cancer. Additionally, CAR-natural killer (NK), CAR-macrophages (M), and TCR-T therapies are currently being researched. In this review, we highlight the current developments and limitations of several types of ACT.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell; Neoplasms; Immunotherapy
PubMed: 38037341
DOI: 10.1177/15330338231204198 -
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 -
American Journal of Hematology May 2019CAR T cells have revolutionized the treatment of relapsed and refractory CD19-positive leukemia and lymphoma. Unfortunately, the majority of patients treated will not... (Review)
Review
CAR T cells have revolutionized the treatment of relapsed and refractory CD19-positive leukemia and lymphoma. Unfortunately, the majority of patients treated will not achieve durable remissions. Reasons for these suboptimal clinical outcomes can be tied back to intrinsic CAR T cell design and manufacturing processes, factors that are highly amenable to modification and improvement. As CAR T cell therapy is being deployed in spaces outside of CD19-positive disease, these limitations, complications, and setbacks need to be overcome, allowing for the full potential of this novel therapy to be realized. Preclinical work has begun tackling these major roadblocks, paving the way for potentially off-the-shelf products that are safer and more potent. In time, a number of these advances will be translated to the clinic and usher in an era of CARs of the future.
Topics: Forecasting; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 30680777
DOI: 10.1002/ajh.25416