Background CD19-specific chimeric antigen receptor (CAR) T cell therapy has achieved high efficacy in acute lymphoblastic leukemia patients. However, the treatment of acute myeloid leukemia (AML) has remained a particular challenge due to the heterogeneity of AML bearing cells, which renders single antigen targeting CAR T cell therapy ineffective. CLL1 and CD33 are often used as targets for AML CAR T cell therapy. CLL1 is associated with leukemia stem cells and disease relapse, and CD33 is expressed on the bulk AML disease. Previously, we demonstrated the profound anti-tumor activity of CLL1-CD33 compound CAR (cCAR) T cells. Here we present the efficacy of cCAR in preclinical study and update the success in level 1 dose escalation clinical trial on relapsed/refractory AML patients. Methods We engineered a cCAR comprising of an anti-CLL1 CAR linked to an anti- CD33 CAR via a self-cleaving P2A peptide and expressing both functional CAR molecules on the surface of a T-cell cell. We tested the anti-leukemic activities of CLL1-CD33 cCAR using multiple AML cell lines, primary human AML samples, human leukemia cell line (REH cells) expressing either CLL1 or CD33, and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with relapsed/refractory AML were enrolled in our phase 1 dose escalation trial with primary objective to evaluate the safety of cCAR and secondary objective to assess the efficacy of cCAR anti-tumor activity. Results Co-culture assays results showed that cCAR displayed profound tumor killing effects in AML cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that cCAR, targeting two discrete AML antigens: CLL1 and CD33, is an effective two-pronged approach in treating bulk AML disease and eradicating leukemia stem cells. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to cCAR treatment. Noticeably, a 6-yr-old female patient diagnosed with a complex karyotype AML including FLT3-ITD mutation had achieved complete remission. The patient was diagnosed with Fanconi anemia, which had progressed to juvenile myelomonocytic leukemia and eventually transformed into AML. The patient had been resistant to multiple lines of treatments, including 5 cycles of chemotherapy with FLT3 inhibitor prior to receiving cCAR. Before the treatment, patient's leukemia blasts comprised 73% of the peripheral blood mononuclear cells and 81% of the bone marrow. Patient underwent lymphodepletion therapy (Fludarabine and Cyclophosphamide) prior to cCAR infusion. Two split doses, each consisting of 1x106/kg CAR T cells, were infused on day 1 and day 2 respectively. On day 12, while leukemia blast still counting up to 98% of the bone marrow (Fig. 1A), robust CAR T cell expansion was detected in both peripheral blood and bone marrow. On day 19, patient achieved MRD- complete remission with bone marrow aspirates revealing complete ablation of myeloid cells (Fig. 1B). Flow cytometry confirmed the absence of leukemia blasts and showed that CAR T cells comprised 36% of the PBMC and 60% of the bone marrow. The patient later underwent non-myeloablative hematopoietic cell transplantation with less toxicities compared to conventional total body radiation and high dose chemotherapies. Updated results on other patients enrolled in this clinical trial including adverse events will be presented. Conclusion Our first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total body radiation or high dose chemotherapies. In addition to AML, cCAR also has the potential to treat blast crisis developed from myelodysplastic syndrome, chronic myeloid leukemia, and chronic myeloproliferative neoplasm. Disclosures Pinz: iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Chen:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC, iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.
Background CD19 CAR T cell therapy has achieved success in treating acute lymphoblastic leukemia. However, the treatment for Sezary syndrome, an aggressive form of cutaneous peripheral T cell lymphoma (PTCL) has remained a challenge. Despite patients with Sezary syndrome typically receiving multiple treatments within their disease progression, the prognosis is poor with 5 year survival rate of only 24%. Therefore, it is crucial to establish a novel treatment for PTCLs. CD4 is uniformly expressed on most mature T cell lymphoma, which makes it a promising target for treating PTCLs. Here, we present the efficacy of CD4 CAR T cell in our preclinical study and the success in level 1 dose escalation clinical trial on patients with Sezary syndrome. Methods We engineered a CD4 CAR with scFv (single-chain variable fragment) with CD28 and 4-1BB co-activators fused to CD3zeta and a leader sequence of CD8. The efficacy of CD4 CAR was tested with CD4+ leukemic cell line, primary CD4+ PTCL patient samples and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with PTCLs were enrolled in our phase 1 dose escalation trial to evaluate the safety and efficacy of CD4 CAR T cell antitumor activity. Results Coculture assays results showed that CD4 CAR T cells displayed profound tumor killing effects in leukemia cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that CD4 CAR T cells is an effective approach in treating PTCLs. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to CD4 CAR T cells treatment. Noticeably, a 54-yr-old patient diagnosed with Sezary syndrome had achieved complete remission with CD4 CAR T cell therapy. Prior to admission, he had been having symptoms of erythroderma, pruritus and scaling of the skin for over 10 years and had been resistant to multiple lines of chemotherapy. Before the initiation of CAR therapy, patient's body skin has extensive leukemia infiltrate (Fig. 1A) confirmed with skin biopsy (Fig. 1B) with bone marrow and blood comprising 50% leukemic cells (Fig. 1C). Patient received a total dose of 3x10^6 /kg single dose CAR T cells, following which fluconazole and valacyclovir were administrated for infection prophylaxis. Since patient received CD4 CAR T cell infusion, the percentage of CAR T cells (Fig 1. D) in peripheral blood had continue to increase as well as NK cells. (Fig 1. E) On day 13, patient had achieved complete remission with the percentage of leukemia cells in blood decreased to zero (Fig. 1C). On day 28, the appearance of the skin had undergone drastic change from what was before the treatment. Noticeable skin regeneration on both legs of the patients was observed (Fig 1. F). Flow cytometry of bone marrow and peripheral blood confirmed the absence of tumor cells. In addition, Skin biopsy on multiple sites demonstrated absence of leukemia infiltrates post CAR treatment (Fig. 1G). Patient was subsequently discharged with no additional medication needed. Throughout the treatment, patient had developed no infections with Grade II CRS toxicity noted. No other toxicities were observed. Updated results on other patients enrolled in this clinical trial including adverse events will be presented. Conclusion Our first-in-human clinical trial demonstrates promising efficacy of CD4 CAR T cell therapy in treating patients with refractory Sezary syndrome. cCAR is able to eradicate leukemia blasts, exerting a profound tumor killing effect that is superior to traditional chemotherapies. Disclosures Pinz: iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Consultancy, Equity Ownership, Research Funding; iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.
Background HLA donor-specific antibodies (DSAs) are preformed antibodies found in recipients against donor's HLA antigens. HLA DSAs are generated through the activation of B cells, which differentiate into specific plasma cells for a given recipient HLA determinant. The existence of HLA DSAs forms a significant barrier to the success of allogenic hematopoietic stem cell transplantation (AHSCT) because HLA DSAs are known to cause primary graft failure (PGF). Rates of primary graft failure (PGF) with DSAs have been reported to be between 24 to 83%, and the highest rates are seen in haplo-identical and cord blood transplantation recipients. Currently, there has not been an established method of depleting DSAs due to the long half life of plasma cells. Since there has been an increasing number of alternative or HLA-mismatched AHSCT performed in hematologic malignancies, it is crucial to develop a feasible way of eliminating DSAs in recipients of AHSCT. CD19 CAR T cells, which have achieved great success in treating B cell malignancies, were shown to have profound efficacy of treating B cell related autoimmune disorders such as lupus in recent mouse model preclinical studies. However, plasma cells were spared in the treatment of lupus with single target CD19 CAR T cells. Additionally, peripheral circulating anti-DNA IgG and IgM autoantibodies remain elevated or increased in treated mice. Here we present the efficacy of BCMA-CD19 compound CAR (cCAR), which target both B cells and plasma cells, in preclinical study and in our first-in-human phase 1 clinical trial. Method We constructed a BCMA-CD19 cCAR, which is a 2-unit CAR composed of a complete BCMA-CAR fused to a complete CD19-CAR by a self-cleaving P2A peptide, enabling independent expression of both CAR receptors separately on the T-cell surface. We then assessed the functional activity of cCAR in co-culture assay with multiple cell lines. We also verified cCAR efficacy with two mouse models each injected with either BCMA-expressing MM.1S cells or CD19-expressing REH tumor cells. In our phase 1 clinical trial, we enrolled children and adults with B-ALL planning to undergo stem cell transplant but were excluded due to high titers of DSAs. Results BCMA-CD19 CAR T-cells exhibited robust cytotoxic activity against the K562 tumor cell line, which is synthetically expressing CD19 or BCMA surface antigen, in co-culture assays. These results indicate the ability of each complete CAR domain to specifically lyse target cells. In mouse model study, BCMA-CD19 CAR T cells were able to eliminate myeloma cells in mice injected with MM.1S cells (multiple myeloma cell line) and deplete REH tumor burden in mice injected with REH cells (B acute lymphoblastic cell line). Our preclinical results demonstrated that both components of the compound CAR, BCMA and CD19, are specifically and equally lysing B cells and plasma cells in vivo, making BCMA-CD19 cCAR a candidate for clinical use. In our first-in-human clinical trial, a 48 yr old female patient having treatment resistant B-ALL with high DSA titers achieved remarkable reduction of DSA titer levels following a single dose of BCMA-CD19 cCAR T cells. Patient exhibited complete remission of B-ALL at day 14 post-CAR T cells. Leukemic cells, normal B cells and plasma cells in bone marrow were undetectable by flow cytometry analysis. Total IgM dropped by 80% 2 weeks post-CAR. Eight different DSA antibody titers were also significantly decreased. At 8 weeks post-CAR, all DSA antibodies titers that we examined were reduced by approximately 80% (Figure 1). Updated results in our phase 1 clinical trial will be presented. Conclusion Our first in human clinical trial on BCMA-CD19 cCAR demonstrated profound efficacy in reducing DSA levels in patients with B-ALL, which made them eligible candidates for stem cell transplant. Our results further suggested that BCMA-CD19 cCAR has the potential to be applied beyond the realm of hematological diseases and can benefit patients receiving solid organ transplants or those with other antibody-mediated diseases such as lupus, multiple sclerosis and ANCA related autoimmune disorders including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), or eosinophilic granulomatosis with polyangiitis (EGPA). Disclosures Ma: iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Consultancy, Equity Ownership, Research Funding; iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.
Introduction: Cancer treatment is complex and necessitates a multidisciplinary approach. Tumour Board Meetings (TBMs) provide a multidisciplinary platform for health care providers to communicate about treatment plans for patients. TBMs improve patient care, treatment outcomes and, ultimately, patient satisfaction by facilitating information exchange and regular communication among all parties involved in a patient's treatment. This study describes the current status of case conference meetings in Rwanda including their structure, process and outcomes. Methods:The study included four hospitals providing cancer care in Rwanda. Data gathered included patients' diagnosis, number of attendance and pre-TBM treatment plan, as well as changes made during TBMs, including diagnostic and management plan changes.Results: From 128 meetings that took place at the time of the study, Rwanda Military Hospital hosted 45 (35%) meetings, King Faisal Hospital had 32 (25%), Butare University Teaching Hospital (CHUB) had 32 (25%) and Kigali University Teaching Hospital (CHUK) had 19 (15%). In all hospitals, General Surgery 69 (29%) was the leading speciality in presenting cases. The top three most presented disease site were head and neck 58 (24%), gastrointestinal 28 (16%) and cervix 28 (12%). Most (85% (202/239)) presented cases sought inputs from TBMs on management plan. On average, two oncologists, two general surgeons, one pathologist and one radiologist attended each meeting. Conclusion:TBMs in Rwanda are increasingly getting recognised by clinicians. To influence the quality of cancer care provided to Rwandans, it is crucial to build on this enthusiasm and enhance TBMs conduct and efficiency.
e21563 Background: Circulating tumor DNA (ctDNA) is tumor-derived fragment of DNA circulating in plasma. ctDNA has been used to detect minimal residual disease (MRD) in early-stage cancers after curative intent therapy. However, ctDNA based MRD concept is not investigated in metastatic disease. There is a lack of clarity around optimal timing to stop immune checkpoint inhibitors (ICI) in melanoma and lung cancer patients who have achieved durable response (DR) and MRD may have a role here to select right patients to stop therapy at an optimal time. Methods: This is prospective study on metastatic lung cancer and melanoma patients with DR treated with ICI. DR is identified as objective response (CR/PR) by modified WHO criteria lasting ≥6 months continuously. We utilized Signatera assay by Natera. Signatera uses tissue from original biopsy of the patients and develop multiplex PCR based personalized assay to detect MRD. The level of ctDNA is reported in mean tumor molecules per mL. We obtained ctDNA assay at baseline, month 3 and month 6 at their routine follow up visits. If applicable, ctDNA assay was done at the time of progression, and 3 months after resuming treatment. Results: We identified 29 melanoma and 17 Lung cancer (both small cell and non-small cell) patients with metastases and DR. Median age was 69 years in both cohorts. Median duration of ICI was 14 months in melanoma and 24 months in lung cancer cohort. ctDNA assay was obtained in 26 melanoma and 13 lung cancer patients. One small cell lung cancer patient had detectable ctDNA at baseline, although radiographically, the patient had DR. The rest of the patients in both cohorts had undetectable ctDNA. 2 melanoma patients developed detectable ctDNA on subsequent assays and their therapies were changed. One small cell lung cancer patient has persistently detectable ctDNA on subsequent assays but remained in DR. A total of 10 patients in both cohorts decided to stop their therapy following several -ve ctDNA assay. Conclusions: The role of ctDNA needs to be investigated in advanced/metastatic settings as MRD may have a role to identify patients who may benefit from treatment break. MRD surveillance may also support radiographic assessment. [Table: see text]
e13520 Background: Due to limited access to healthcare providers, lengthy travel times to clinics, and disadvantageous socioeconomic dynamics, patients in rural locations face significant challenges causing a low recruitment in clinical trials. However, there may be preconceived assumptions of a patient’s desire to participate in a trial leading to bias from healthcare organizations and thereby, decreased efforts in enrollment. Dartmouth Cancer Center is the smallest NCI designated comprehensive cancer center, serving rural New Hampshire and Vermont. In this study, we surveyed patients with cancer to assess their level of understanding of clinical trials, factors influencing patients’ willingness to enroll, and the difficulties faced after accrual in the trials. Methods: A 23 items anonymous questionnaire was distributed to the oncology patients at the outpatient clinic. The questions included demographics, socioeconomic status, time to travel, challenges faced in participating in the trials. Cox proportional regression analysis was done to identify factors influencing decision to participate in trials. Results: Among 93 respondents, 74% are within the age of 61 – 80 years, 64.45% are male and 74% are married, 51% are retired and 59.7% have household income of ≤$100,000. 32.2% of our respondents travelled over 1 hour to receive care. 73.3% of the respondents understood what it means to participate in a clinical trial. 91.8% are willing, yet only 40% were given an option to participate in a trial. Only 10.5% ever declined to participate. Additional cost, frequent travel, and possibility of receiving a placebo are the biggest factors in declining a participation. Up to 95% of the participants enrolled in a trial had positive experience and have the ultraistic motives. None of the socioeconomic or personal factors had any significant bearing on willingness to participate. Conclusions: Socioeconomic and regional factors have little bearing on a person's inclination to participate in clinical trials. There is a strong interest in understanding and enrolling in clinical studies. Cancer centers need to reduce the gap between patient interest in trials and actual trial participation.[Table: see text]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.