Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study

Abstract The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions. 

Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

The immune system is essential in recognizing and eliminating tumor cells. The unique characteristics of the tumor microenvironment (TME), such as heterogeneity, reduced blood flow, hypoxia, and acidity, can reduce the efficacy of cell-mediated immunity. The primary goal of cancer immunotherapy is to modify the immune cells or the TME to enable the immune system to eliminate malignancies successfully. Nanobodies, known as single-domain antibodies, are light chain-free antibody fragments produced from Camelidae antibodies. The unique properties of nanobodies, including high stability, reduced immunogenicity, enhanced infiltration into the TME of solid tumors and facile genetic engineering have led to their promising application in cell-mediated immunotherapy. They can promote the cancer therapy either directly by bridging between tumor cells and immune cells and by targeting cancer cells using immune cell-bound nanobodies or indirectly by blocking the inhibitory ligands/receptors. The T-cell activation can be engaged through anti-CD3 and anti-4-1BB nanobodies in the bispecific (bispecific T-cell engagers (BiTEs)) and trispecific (trispecific T-cell engager (TriTEs)) manners. Also, nanobodies can be used as natural killer (NK) cell engagers (BiKEs, TriKEs, and TetraKEs) to create an immune synapse between the tumor and NK cells. Nanobodies can redirect immune cells to attack tumor cells through a chimeric antigen receptor (CAR) incorporating a nanobody against the target antigen. Various cancer antigens have been targeted by nanobody-based CAR-T and CAR-NK cells for treating both hematological and solid malignancies. They can also cause the continuation of immune surveillance against tumor cells by stopping inappropriate inhibition of immune checkpoints. Other roles of nanobodies in cell-mediated cancer immunotherapy include reprogramming macrophages to reduce metastasis and angiogenesis, as well as preventing the severe side effects occurring in cell-mediated immunotherapy. Here, we highlight the critical functions of various immune cells, including T cells, NK cells, and macrophages in the TME, and discuss newly developed immunotherapy methods based on the targeted manipulation of immune cells and TME with nanobodies.

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1012841/pdf

Nanobodies in cell-mediated immunotherapy: On the road to fight cancer

T-cell malignancies can be divided into precursor (T-acute lymphoblastic leukemia/lymphoblastic lymphoma, T-ALL/LBL) and mature T-cell neoplasms, which are comprised of 28 different entities. Most of these malignancies are aggressive with rather poor prognosis. Prognosis of relapsed/refractory (R/R) disease is especially dismal, with an expected survival only several months after progression. Targeted therapies, such as antiCD30 immunotoxin brentuximab vedotin, antiCD38 antibody daratumumab, and anti-CCR4 antibody mogamulizumab are effective only in subsets of patients with T-cell neoplasms. T-cells equipped with chimeric antigen receptor (CAR-Ts) are routinely used for treatment of R/R B-cell malignancies, however, there are specific obstacles for their use in T-cell leukemias and lymphomas which are fratricide killing, risk of transfection of malignant cells, and T-cell aplasia. The solution for these problems relies on target antigen selection, CRISPR/Cas9 or TALEN gene editing, posttranslational regulation of CAR-T surface antigen expression, and safety switches. Structural chromosomal changes and global changes in gene expression were observed with gene-edited products. We identified 49 studies of CAR-based therapies registered on www.clinicaltrials.gov. Most of them target CD30 or CD7 antigen. Results are available only for a minority of these studies. In general, clinical responses are above 50% but reported follow-up is very short. Specific toxicities of CAR-based therapies, namely cytokine release syndrome (CRS), seem to be connected with the antigen of interest and source of cells for manufacturing. CRS is more frequent in antiCD7 CAR-T cells than in antiCD30 cells, but it is mild in most patients. More severe CRS was observed after gene-edited allogeneic CAR-T cells. Immune effector cell associated neurotoxicity (ICANS) was mild and infrequent. Graft-versus-host disease (GvHD) after allogeneic CAR-T cells from previous hematopoietic stem cell donor was also observed. Most frequent toxicities, similarly to antiCD19 CAR-T cells, are cytopenias. CAR-based cellular therapy seems feasible and effective for T-cell malignancies, however, the optimal design of CAR-based products is still unknown and long-term follow-up is needed for evaluation of their true potential.

/pdf/chimeric-antigen-receptor-based-cellular-therapy-for-1tkzprkf.pdf

Chimeric Antigen Receptor Based Cellular Therapy for Treatment Of T-Cell Malignancies

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis despite the advent of novel therapies. Consequently, a major need exists for new therapeutic options, particularly for patients with relapsed/refractory (R/R) AML. In recent years, it has been possible to individualize the treatment of a subgroup of patients, particularly with the emergence of multiple targeted therapies. Nonetheless, a considerable number of patients remain without therapeutic options, and overall prognosis remains poor because of a high rate of disease relapse. In this sense, cellular therapies, especially chimeric antigen receptor (CAR)-T cell therapy, have dramatically shifted the therapeutic options for other hematologic malignancies, such as diffuse large B cell lymphoma and acute lymphoblastic leukemia. In contrast, effectively treating AML with CAR-based immunotherapy poses major biological and clinical challenges, most of them derived from the unmet need to identify target antigens with expression restricted to the AML blast without compromising the viability of the normal hematopoietic stem cell counterpart. Although those limitations have hampered CAR-T cell therapy translation to the clinic, there are several clinical trials where target antigens, such as CD123, CLL-1 or CD33 are being used to treat AML patients showing promising results. Moreover, there are continuing efforts to enhance the specificity and efficacy of CAR-T cell therapy in AML. These endeavors encompass the exploration of novel avenues, including the development of dual CAR-T cells and next-generation CAR-T cells, as well as the utilization of gene editing tools to mitigate off-tumor toxicities. In this review, we will summarize the ongoing clinical studies and the early clinical results reported with CAR-T cells in AML, as well as highlight CAR-T cell limitations and the most recent approaches to overcome these barriers. We will also discuss how and when CAR-T cells should be used in the context of AML.

Chimeric antigen receptor (CAR) modified T Cells in acute myeloid leukemia: limitations and expectations

S187: updated phase 1/2 data of safety and efficacy of ct103a, fully human bcma-directed car t cells, in relapsed/refractory multiple myeloma

Background: Donor derived CD19 car T cells plus donor lymphocyte infusion is rarely used in the treatment of recurrent CD19 positive B-ALL after allogeneic hematopoietic stem cell transplantation (allo-HSCT) Aims: To compare the efficacy of donor derived CD19 car T cells and chemotherapy plus donor lymphocyte infusion in the treatment of recurrent CD19 positive B-ALL after allogeneic hematopoietic stem cell transplantation (allo-HSCT) Methods: We retrospectively analyzed 43 patients with B-ALL who relapsed after allo-HSCT from March 2016 to November 2019，including 22 patients treated with donor derived CD19-CAR-T cells (CAR-T group) and 21 patients treated with chemotherapy plus donor lymphocyte infusion (Chemo-DLI group). Results: The rates of complete remission (77.3%) in the CAR-T group were significantly higher than those in the Chemo- DLI group (38.1%); The 1- and 2-year leukemia-free survival(LFS) in the CAR-T group and Chemo-DLI group were 54.5% vs 9.5%, 45.5% vs 4.8%, respectively. The 1- and 2-year overall survival(OS) in the CAR-T group and Chemo-DLI group were 68.2% vs 19%, 63.6%vs 9.5%, respectively. Six patients (28.6%) in the Chemo-DLI group developed grade II-IV acute graft-versus-host disease (aGVHD). Two patients (9.1%) with grade I-II aGVHD were found in the CAR-T group. The incidence of CRS in the CAR-T group was 86.4%, the grade I-II CRS was59.1%, the grade III CRS was 27.3%. There was no grade 4 CRS. Two subjects developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Summary/Conclusion: Compared with chemotherapy plus DLI, donor-derived CD19 CAR-T is more effective and safe in the treatment of recurrent B-ALL after allogeneic HSCT. 

P364: donor-derived cd19 car-t cells and chemotherapy plus donor lymphocyte infusion in the treatment of recurrent cd19+ b-all after allogeneic hematopoietic stem cell transplantation

Background: Background: There is no standard induction chenotherapy for adult acute lymphoblastic leukemia. Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has poor response to standard intensive chemotherapy, high risk of recurrence and poor prognosis. Aims: Aims: To explore the appropriate induction program to improve the remission rate and prolong the survival period. Methods: Methods: A total of 21 newly diagnosed patients with ETP-ALL who received induction chemotherapy with different regimens in the Second Affiliated Hospital of Chongqing Army Military Medical University (Xinqiao Hospital) from January 2017 to December 2020 were retrospectively analyzed for efficacy and main adverse r eactions.The initial diagnosis of ETP-ALL was based on the results of bone marrow cytology and flow cytometry immunophenotype. Results: Results: The 21 patients included 14 males and 7 females, with a median age of 27(16-57) years. Among them, 7 patients received PCIOD program and 14 patients received VTLP like program.Among the 7 patients who received PCIOD, 5 patients achieved cytological response (71.43%), and 2 patients were MRD negative (28.57%).In VTLP-like regimen, 7 patients (50%) had cytological remission, of which 1 patient (7.14%) was MRD negative.Major adverse reactions: bone marrow suppression, granulocytopia with fever and septicemia were the major adverse reactions after chemotherapy.Among the 7 patients with PCIOD, 3 patients developed pulmonary infection, including 1 patient with sepsis (klebsiella pneumoniae), while 5 patients with VTLP-like regimen developed pulmonary infection, 3 patients with sepsis, and 2

Pb1765: efficacy of a new induction regimen in the treatment of early t-cell precursor acute lymphoblastic leukemia.

Background: Prognosis of refractory and relapsed acute myeloid leukemia (r/r AML) is challenge and no standard of treatment exists. Cladribine based regimen in treatment of r/r AML proved to be effective,while the total rate of response is limited. Aims: To explore whether the addition of liposomal adriamycin can improve the response. Methods: We registered a clinical trial, which is CLAG plus liposomal adriamycin (CLAG+PLD) regimen for re-induction of r/r AML (ChiCTR1800017569), to observe the response, overall survival (OS) and disease free suivival (DFS) of the patients. In addition to that, CLAG alone as salvage therapy (no PLD group) for RR-AML in our medical center were chosen as historical comparison Results: To observe the response, overall survival (OS) and disease free suivival (DFS) of the patients. In addition to that, CLAG alone as salvage therapy (no PLD group) for RR-AML in our medical center were chosen as historical comparison.Of the 55 patients who were evaluable for remission after CLAG +PLD treatment(PLD group), 27（49.1%）achieved CR and negative of MRD, 12（21.8%）achieved CR and positive of MRD, 5（9.1%）achieved partial response, and 11（20%）no response. In Contrast, no PLD group has inferior response rate,with the corresponding data is 24（46.6%）, 6（10.9%）,10（18.2%）,and 13（23.6%）respectively (p= 0.008).As for the 2-year OS and DFS, the median OS and DFS for PLD group has not reached and 10 months for noPLD group (p= 0.023 and p= 0.045 respectively). The safety observation did not find increasing toxicity in PLD group.In subgroup analysis of PLD group, the response between FLT3-ITD mutated group and wild group showed significant difference (p=0.006). Moreover, hematopoietic stem cell transplantation (HSCT) group exert superiority in both OS and DFS compared to no HSCT group with 2-year of follow-up（p＜0.0001 and p＜0.00001 respectively）. Image:Summary/Conclusion: In conclusion, CLAG + PLD is a prospective salvage regimen for r/r AML which brings improved response rates, 2-year OS and DFS and similar toxicities compared to CLAG. 

P588: improved outcome of relapsed/refractory acute myeloid leukemia by addition of liposomal adriamycin to clag chemotherapy

[Vedolizumab for treatment of steroid-refractory intestinal acute graft-versus-host disease: two cases report and literature review].

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