Refractory Hematologic Malignancies Research Articles

#5525 NEPHROTOXICITY OF CHIMERIC ANTIGEN RECEPTOR T CELL (CAR-T) THERAPY: ACUTE KIDNEY INJURY AND ELECTROLYTE DISORDERS

Abstract Background and Aims Chimeric antigen receptor T cell therapy (CAR-T) has improved the prognosis of patients with refractory hematologic malignancies. The most important toxicities are the cytokine release syndrome (CRS), where interleukin 6 (IL-6) plays a major role, and the immune effector cell-associated neurotoxicity syndrome (ICANS). A low incidence of acute kidney injury (AKI) with a high frequency of electrolyte imbalance has been described with CAR-T therapy. The aim of our study is to describe the nephrotoxicity of CAR-T therapy and to focus on AKI and the physiopathology of hypophosphatemia. Method A prospective single-center case series was performed which included all patients undergoing CAR-T therapy between 2020 and 2022. Clinical data included medical history, previous chemotherapy treatments, concomitant treatments, and clinical evolution. Daily monitoring of renal function, electrolytes and IL-6 was obtained after infusion of CAR-T. A urine sample was obtained on days 0, +7 and +14 with parathyroid hormone (PTH) and 25-OH vitamin D. AKI was classified according to the KDIGO criteria. Results 40 patients received CAR-T therapy during the follow-up period. The median age was 62 years. The same number of men as women were included. The most frequent comorbidities were hypertension (27.5%), followed by diabetes (12.5%) and chronic kidney disease (12.5%). 12 patients presented AKI. Baseline serum creatinine (SCr) in patients with AKI was 0.9 mg/dL (0.68-1.04) with a SCr peak of 1.27 mg/dL (1.1-1.7). The time from CAR-T therapy infusion to SCr peak was 6.5 days (4-10). Of these 12 patients, 8 presented stage 1, 3 stage 2, and 1 stage 3 AKI. There were no differences between the AKI and non-AKI group in baseline characteristics, inflammatory markers, CRS, ICANS or hospital length stay. Hypophosphatemia was the most frequent electrolyte imbalance, occurring in 36 patients (90 %), 22 (61 %) patients experienced moderate hypophosphatemia (phosphorus < 2 mg/dL) while 14 (39 %) patients experienced mild hypophosphatemia. 29 patients (72 %) presented hypokalemia and 25 patients (62.5 %) hyponatremia. Patients with moderate hypophosphatemia had a significantly higher elevation of IL-6 but there were no differences in PTH or vitamin D (Table 1). Although there were no significant differences in fractional excretion of filtered phosphate (FEPO4), patients with moderate hypophosphatemia trend to have higher FEPO4 values. Conclusion Electrolyte disturbances are common in CAR-T therapy, with hypophosphatemia being the most frequent. There is probably a mechanism for renal phosphorus loss related to systemic inflammation. AKI is less frequent and has mild characteristics in these patients.

#5213 RELATIONSHIP BETWEEN CYTOKINE RELEASE SYNDROME AND ACUTE KIDNEY INJURY AFTER CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY IN HEMATOLOGIC NEOPLASMS

Abstract Background and Aims CAR-T cell therapy is a promising new immunotherapy to treat refractory hematologic malignancies (RHM). Despite the potential benefits, high rates of treatment related toxicity have been reported after CAR-T infusion. AKI occurs between 20-30% after treatment. The purpose of this study was to identify the relationship between the proinflammatory status (CRS, ICANs, and febrile neutropenia) and AKI development. Method Medical records of 115 patients treated with CD19-targeted CAR-T cells for refractory hematologic malignancies at HUVH between July 2018 and May 2021 were reviewed. Clinical data was reviewed within 30 days after CAR-T cells therapy. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria: grade 1, 1.5 to <2-fold of baseline; grade 2, 2- to <3-fold of baseline; grade 3, ≥3-fold of baseline We performed statistically analysis to identify risk factors for AKI development. Results A total of 24/115 patients presented AKI after CAR-T infusion. AKI Akin stage 1 was diagnosed in 17 (15%) patients, AKI Akin stage 2 was diagnosed in 4 (3.5%) patients, and AKI Akin stage 3 was diagnosed in 3 (2.6%) patients. 4/17 patients died in the AKI Akin stage 1 group while 2/3 patients in the AKI Akin stage 3 group. Renal function was recovered in 19/24 (79%) patients within the first month. Chronic kidney disease was present in 13% patients. Among types of CAR-T cell infusion, “investigational product” was infused in 27.8%, tisagenlecleucel in 49.6%, axicabtagen ciloleucelin in 20%, and brexucabtagene autoleucel in 2.6%. The most frequent complications were cytokine release syndrome (81.9%), febrile neutropenia (67%) and neurotoxicity (28.7%). Tocilizumab was given in 31 (27%) patients for CRS grade ≥2, and 5% of patients were admitted to the intensive care unit 3/36 patients died after CAR-T infusion. Male sex, CAR T-cell construct, ICANs, CRS, and death by any cause were associated with AKI. Only CRS ≥2(p=0.001) was identified as independent risk factor for AKI. Conclusion AKI development is mainly transient and associated with the proinflammatory status after CAR-T cell infusion.

Systemic VSV-IFNβ-NIS oncolytic virotherapy in patients with relapsed refractory T-cell lymphoma.

7530 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach currently under study for relapsed refractory (R/R) hematologic malignancies. The engineered Vesicular Stomatitis Virus VSV-IFNβ-NIS used in this study encodes interferon beta (IFNβ) and sodium iodine symporter (NIS). Virally-encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. Herein, we report the updated results of the phase 1 clinical trial NCT03017820 of a one-time administration of systemic VSV-IFNβ-NIS among patients (pts) with R/R multiple myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML) with particular focus on the TCL cohort treated at the highest dose level (DL4) without Ruxolitinib. Methods: VSV-IFNβ-NIS was administered as a single IV dose following a classical 3+3 phase I trial, starting at 5e9 TCID50 DL1 through 1.7e11 TCID50 DL4. A dose expansion cohort of 8 additional R/R TCL pts was added at DL4 in view of an initial signal of activity. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: To date, a total of 43 pts received VSV-IFNβ-NIS: MM (N=21), TCL (N=21) and AML (N=1). In the TCL cohort: at DL4 Group A (no Ruxolitinib), 12 pts were registered, but only 11 pts were treated (mycosis fungoides (MF) N=3; ALK- ALCL N=1; PTCL-NOS N=2; AITL N=4; Nodal PTCL, TFH N=2; ages 33-79). These pts received a median of 3 lines of therapy (range: 1-5). No dose limiting toxicities were observed. Grades 3 and higher AEs were hematologic with transient lymphopenia (63.6%), neutropenia (36.4%) being the most common. The non-hematologic AEs observed included unique toxicities such as CRS grades 1-2 (81.8%); the transient transaminitis grade 1-2 (36.4%) and grade 3 (27.3%) along with thrombocytopenia grade 1-2 (63.6%) and grade 3 (18.2%) were a reflection IFNβ toxicity. All the AEs observed were short lived. Responses were seen in pts with PTCL. At DL4, in pts with systemic PTCL (N=9), there were 5 responses including 3 complete responses (CR) with two long-lasting at 24 months, an ongoing 15 month CR, and a 5 month CR, and 2 partial responses (PR) lasting 5 months in one pts and 6 months in the other. Conclusions: These updated results of single agent VSV-IFNβ-NIS which include pts with PTCL treated at the highest dose level and a dose expansion cohort demonstrates not only the safety of VSV-IFNβ-NIS but also a strong efficacy signal in pts with PTCL with impressive durable responses. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma pts) to obtain additional data on tolerability and efficacy and biomarkers of response in these pts. Clinical trial information: NCT03017820 .

Preliminary pharmacokinetic and safety data after a single intravenous infusion of Voyager-V1 (VV1, VSV-IFNβ-NIS) oncolytic virus in patients with relapsed refractory hematologic malignancies.

e14594 Background: Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express interferon beta (IFNβ) to boost cellular antitumor immunity and sodium iodine symporter (NIS). A phase 1 trial investigating a single infusion of VV1 in patients with relapsed refractory multiple myeloma and T-cell lymphoma (TCL) showed promising and durable clinical activity, primarily in patients with TCL. VV1 infects tumor cells and macrophages in the lymph nodes and spleen, resulting in release of tumor antigens and IFNβ that activates and boost cellular antitumor immunity. We present the preliminary pharmacokinetic analysis in patients given one intravenous (IV) dose of VV1. Methods: Patients received 5e9 to 1.7e11 TCID50 (50% tissue culture infective dose) of VV1 given over 30 minutes. We also explored the impact of infusion duration (0.25, 0.5,1 and 3 hours) in 17 patients with solid tumors. The objectives were to determine the impact of viral dose on pharmacokinetics (PK) of VSV and IFNβ. For VSV and IFNβ PK, whole blood was collected in 30 patients on days 1, 2, 3, and 8. Dose levels were 1.7E10, 5E10, and 1.7E11 TCID50. The plasma concentration-time data were estimated with non-compartmental analysis using WinNonlin 8.3. Results: The half-life of VV1 is comparable (10-12h) between dose levels of 1.7e10, 5e10 and 1.7e11. Ideal infusion rate was found to be 30 minutes and provides the highest Cmax and AUC. Most peak concentrations for viremia and IFNβ were achieved between ‘end of infusion’ and 2.5 hours, 4.5 and 24 hours, respectively. Following infusion, a second concentration peak is found in over half the patients leading to highly variable terminal elimination half-life, specifically where the second peak is at 24 hours. There was no second peak for IFNβ levels. Peak plasma concentration and systemic exposure increased in proportion to increased dose, consistent with linear clearance. Conclusions: The 30 minute infusion rate was considered the best as its PK provides the highest Cmax and AUC with no significant CRS differences among other groups. IL-6 and IFNα markers at hour 4 indicate a likely CRS and hour 24 provides a possible prediction of the grade. Cmax and AUC were also highest at 1.7e11 TCID50. This is the recommended dose that will be used in the expansion arm in patients with TCL. Clinical trial information: NCT03017820 , NCT02923466 . [Table: see text]

Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review).

Chimeric antigen receptor (CAR) T cell therapy has emerged as a new and breakthrough cancer immunotherapy. Although CAR-T cell therapy has made significant progress clinically in patients with refractory or drug-resistant hematological malignancies, there are numerous challenges in its application to solid tumor therapy, including antigen escape, severe toxic reactions, abnormal vascularization, tumor hypoxia, insufficient infiltration of CAR-T cells and immunosuppression. As a conventional mode of anti-tumor therapy, radiotherapy has shown promising effects in combination with CAR-T cell therapy by enhancing the specific immunity of endogenous target antigens, which promoted the infiltration and expansion of CAR-T cells and improved the hypoxic tumor microenvironment. This review focuses on the obstacles to the application of CAR-T technology in solid tumor therapy, the potential opportunities and challenges of combined radiotherapy and CAR-T cell therapy, and the review of recent literature to evaluate the best combination for the treatment of solid tumors.

Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications.

Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6 FDA approved products target various surface antigens. While CAR-T therapy achieves good response, life-threatening toxicities have been reported. Mechanistically, can be divided into two categories: (1) toxicities related to T-cell activation and release of high levels of cytokines: or (2) toxicities resulting from interaction between CAR and CAR targeted antigen expressed on non-malignant cells (i.e., on-target, off-tumor effects). Variations in conditioning therapies, co-stimulatory domains, CAR T-cell dose and anti-cytokine administration, pose a challenge in distinguishing cytokine mediated related toxicities from on-target, off-tumor toxicities. Timing, frequency, severity, as well as optimal management of CAR T-cell-related toxicities vary significantly between products and are likely to change as newer therapies become available. Currently the FDA approved CARs are targeted towards the B-cell malignancies however the future holds promise of expanding the target to solid tumor malignancies. Further highlighting the importance of early recognition and intervention for early and late onset CAR-T related toxicity. This contemporary review aims to describe presentation, grading and management of commonly encountered toxicities, short- and long-term complications, discuss preventive strategies and resource utilization.

Editing Mutations of GABRB3 Using CRISPR-Cas9 as a Potential Treatment for Epilepsy and Autism Spectrum Disorders

The treatment of a variety of recurrent or resistant hematologic malignancies with chimeric antigen receptor T cell (CAR- T) cell therapy has seen significant success in recent years. The current CAR- T cell therapy approach is not without flaws, nevertheless, and there are still several issues with clinical treatment, including antigen escape, significant toxicity, and sus-ceptibility to drug-resistant recurrence. This paper introduces the structural development and characteristics of CAR-T cells, reviews the limitations of CAR- T cell therapy, including an-tigen escape, toxicity, CAR-T cell depletion and drug-resistant relapse after treatment, and summarizes the related improvement and optimization strategies. The paper concludes that CAR-T cell immunotherapy has brought new hope to patients with hematologic malignancies, making a cure for refractory and recurrent hematologic malignancies possible. Although CAR-T cell therapy still has many challenges at present, such as immunogenicity, drug re-sistance, and toxicity.

Structural and Research Advances in CAR-T Cell Therapy

The treatment of a variety of recurrent or resistant hematologic malignancies with chimeric antigen receptor T cell (CAR- T) cell therapy has seen significant success in recent years. The current CAR- T cell therapy approach is not without flaws, nevertheless, and there are still several issues with clinical treatment, including antigen escape, significant toxicity, and sus-ceptibility to drug-resistant recurrence. This paper introduces the structural development and characteristics of CAR-T cells, reviews the limitations of CAR- T cell therapy, including an-tigen escape, toxicity, CAR-T cell depletion and drug-resistant relapse after treatment, and summarizes the related improvement and optimization strategies. The paper concludes that CAR-T cell immunotherapy has brought new hope to patients with hematologic malignancies, making a cure for refractory and recurrent hematologic malignancies possible. Although CAR-T cell therapy still has many challenges at present, such as immunogenicity, drug re-sistance, and toxicity.

Characterizing EEG and Serum Biomarker Trends in Immune Effector Cell-Associated Neurotoxicity: A Case Series (P10-1.001)

<h3>Objective:</h3> To characterize electroencephalographic (EEG) trends over time in immune effector cell-associated neurotoxicity syndrome (ICANS) and identify correlations between neuron-derived serum biomarkers of inflammation, neurotoxicity grade, and EEG findings. <h3>Background:</h3> Chimeric antigen receptor T-cell therapy (CAR-T) can be effective for refractory hematologic malignancies, but may be complicated by ICANS. Previous studies link higher peak neurotoxicity grades with EEG background abnormalities and higher incidences of rhythmic and periodic patterns (RPPs). <h3>Design/Methods:</h3> We performed a retrospective analysis of CAR-T patients who were enrolled into an IRB-approved prospective, longitudinal observational study. Data including demographics, ICE scores, and neurologic symptoms were prospectively entered. Serum biomarkers including Ang-1, Ang-2, IL-6, UCH-L1, and S100b were drawn prior to CAR-T and at defined time points thereafter. EEG data was reviewed, with encephalopathy grade defined by American Clinical Neurophysiology Society (ACNS) criteria. <h3>Results:</h3> Forty-five patients were included in the study. Ten patients (22%) developed ICANS. EEG data was available for five (11%) patients, with a median of 35 hours recorded per patient. Zero patients had confirmed electrographic seizures. Median ICE score prior to EEG was 1. Backgrounds were mildly or moderately encephalopathic, with improving organization and faster frequencies over time. GPDs or LPDs of 0.5–2Hz were rare to abundant and gradually improved with time. Focal slowing and sharp waves were common. S100b consistently increased above (average 45%) and Ang-2 decreased below (average 53%) baseline at the time of becoming symptomatic for two patients (drawn within 48 hours before/after EEG was obtained), whereas Ang-1, IL-6, and UCH-L1 had more variable changes. <h3>Conclusions:</h3> Patients with ICANS who underwent EEGs had up to moderate electrographic (and severe clinical) encephalopathy and RPPs that spontaneously improved with time. Higher encephalopathy grade occurred in those with greater S100b increases. Our observations will need to be confirmed in an independent population with serial samples and EEG data on all patients. <b>Disclosure:</b> Dr. Nguyen has nothing to disclose. Lila Renteria has nothing to disclose. Dr. Motika has nothing to disclose. Dr. Hinson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Hinson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UCSF. Dr. Hinson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association.

Frontal Intermittent Rhythmic Delta Activity Is a Useful Diagnostic Tool of Neurotoxicity After CAR T-Cell Infusion.

Chimeric antigen receptor (CAR) T-cell therapies have dramatically improved the prognosis of patients with relapsed or refractory hematologic malignancies; however, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) occur in ∼100 and 50% of patients, respectively. This study aimed to determine whether EEG patterns may be considered as diagnostic tools for ICANS. Patients who received CAR T-cell therapy at Montpellier University Hospital between September 2020 and July 2021 were prospectively enrolled. Neurologic signs/symptoms and laboratory parameters were monitored daily for 14 days after CAR T-cell infusion. EEG and brain MRI were performed between day 6 and 8 after CAR T-cell infusion. EEG was performed again on the day of ICANS occurrence, if outside this time window. All collected data were compared between patients with and without ICANS. Thirty-eight consecutive patients were enrolled (14 women; median age: 65 years, interquartile range: [55-74]). ICANS was observed in 17 of 38 patients (44%) after a median time of 6 days after CAR T-cell infusion (4-8). The median ICANS grade was 2 (1-3). Higher C-reactive protein peak (146 mg/L [86-256], p = 0.004) at day 4 (3-6), lower natremia (131 mmol/L [129-132], p = 0.005) at day 5 (3-6), and frontal intermittent rhythmic delta activity (FIRDA, p < 0.001) on EEG between days 6 and 8 after infusion were correlated with ICANS occurrence. FIRDA was only observed in patients with ICANS (N = 15/17, sensitivity of 88%) and disappeared after ICANS resolution, usually after steroid therapy. Except for hyponatremia, no other toxic/metabolic marker was associated with FIRDA (p = 0.002). The plasma concentration of copeptin, a surrogate marker of antidiuretic hormone secretion, assessed at day 7 after infusion, was significantly higher in patients with (N = 8) than without (N = 6) ICANS (p = 0.043). FIRDA is a reliable diagnostic tool for ICANS, with a sensitivity of 88% and a negative predictive value of 100%. Moreover, as this EEG pattern disappeared concomitantly with ICANS resolution, FIRDA could be used to monitor neurotoxicity. Finally, our study suggests a pathogenic pathway that starts with increased C-reactive protein, followed by hyponatremia and eventually ICANS and FIRDA. More studies are required to confirm our results. This study provides Class III evidence that FIRDA on spot EEG accurately distinguishes patients with ICANS compared with those without after CAR T-cell therapy for hematologic malignancy.

Abstract LB218: Developing a bispecific anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment

Abstract Developing a bispecific anti-ROR1 Antibody Drug Conjugate for hematological and solid tumor treatment Receptor tyrosine kinase ROR1 is a type I transmembrane protein belongs to the ROR family members. ROR1 is a receptor for Wnt family signaling molecules Wnt5a and is a key regulator of normal cellular process, including cell proliferation, survival, and migration. It is also involved in the development and progression of many types of cancer. Although being an oncofetal protein with limited expression in most of the normal tissues, ROR1 is expressed abnormally in various hematological and solid cancers, making it a highly attractive target for antibody-drug conjugate (ADC) therapy. The current clinical results of ROR1 ADC have been promising in treating patients with relapsed and/or refractory (R/R) hematologic malignancies. Utilizing our unique and innovated linker platform, we screened many anti-ROR1 ADCs, with defined DAR=4. Those unique ADCs consist of a humanized monoclonal antibody (mAb against single epitope) or a bispecific antibody (BsAb against two epitopes), stably conjugated to an antimitotic agent. The bispecific mAbs that target to two different epitopes of ROR1, are superior to those antibodies that target to single epitope in the binding to ROR1-expressing tumor cells, the induction of tumor cell death and anti-tumor immunity. Our novel linker structure prevents payloads from coming off of the antibody during the circulation, significantly reduced the off-target toxicity. In vitro and In vivo studies demonstrated the antitumor activity of anti-ROR1 ADCs outperformed the lead anti-ROR1 ADC currently in phase II/IIl trial, providing a promising treatment for hematological and solid cancers with a better safety profile and a larger therapeutic window. The lead candidate molecule, BR111A will start the preclinical studies soon. Citation Format: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Jing Li, yaqiong zhou, Lei Nie, Gang Chen. Developing a bispecific anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB218.

Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid-Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π-π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro-apoptotic reactions by promoting the dissociation of the pro-apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor-loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2 O2 -triggered drug release, and significant cytotoxicity toward MOLM-13-Luc and MV-411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45ng mL-1 , respectively. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment.

Management of adverse effects in CAR T-cell therapy

Immunotherapies such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy are emerging as new treatments for relapsed and/or refractory hematological malignancies. CAR T-cell therapy has attracted attention as a potentially curative treatment for patients incurable by chemotherapy. However, appropriate management is required to avoid serious complications specific to CAR T-cell therapy, such as cytokine release syndrome (CRS), neurotoxicity (ICANS), hypogammaglobulinemia and prolonged cytopenia, as well as post-treatment infections caused by suppressed immune function.

Metformin as a therapeutic tool for resistant hematological malignancies: a literature review.

Hematological malignancies (HMs) are a group of neoplasms with hematopoietic origin, currently divided into leukemias, lymphomas and multiple myeloma (MM). Although the advances in the management of HMs, the rate of drug resistance, relapse and refractory disease has been increasing, requiring new therapeutic strategies. In this review, we aim to summarize metformin's antitumoral mechanisms of action and present the latest studies of metformin action in HMs, including in resistant ones. For this review of literature, studies published between 1996 and 2023 from PubMed and clinical trials submitted to clinicaltrials.gov were considered. Throughout this review we demonstrated the capacity of metformin to act as an anti-HMs drug, being able to re-sensitize HMs to classical anti-HMs agents and to overcome relapse and refractory HMs, as shown in vitro and in vivo studies. Associated with the potential anti-HM effect of metformin, some clinical trials are in progress, including in the view of reducing resistance and recurrence rate of HMs, which requires further exploration. The relationship among HMs cancer stem cells (HMs CSCs), drug resistance, cancer recurrence, and the effect of metformin in inhibiting CSCs were also discussed, despite this field needing more attention. In summary, metformin is a promising anti-HMs drug that can enhance patients' survival and prognosis through its action in the improvement of HMs response.

2097. Bacterial Infections in the Setting of Late Neutropenia Following CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Non-Hodgkin Lymphoma (NHL)

Abstract Background Cellular therapies such as CAR-T therapy have excellent clinical efficacy for treatment of relapsed and refractory hematologic malignancies. Late neutropenia, occurring more than 30 days after CAR-T cell infusion, is a frequent complication, though its impact on infection risk is not well understood. Methods We performed a retrospective study of 280 adults receiving CD19 CAR-T therapy for NHL between December 2017 and September 2021 (n=280). Levofloxacin prophylaxis was used after CAR-T infusion until initial count recovery (absolute neutrophil count (ANC) ≥ 1000). Patients were evaluated for late neutropenia with ANC &amp;lt; 1000 during three time periods following cell infusion: day 30 – 100; day 100 – 365; and after day 365. Infections were recorded if there was a microbiologic diagnosis with correlating symptoms and treatment. Infection severity was determined using Blood and Marrow Transplant Clinical Trials Network criteria. Patients were censored on the first day of any additional antineoplastic therapy after relapse, death or last follow up until 1/25/2022. Results Of 280 patients with NHL who received CAR-T therapy, 116 (41%) had late neutropenia. Baseline characteristics and early CAR-T toxicities are shown in Table 1. Amongst patients with late neutropenia, 11 (9%) developed a bacterial infection during late neutropenia and 3 (3%) developed Clostridioides difficile infection. The most frequent infection site was the bloodstream (n=5), followed by the urinary tract (UTI; n=4). Most infections were moderate in severity (n = 9, 64%), though several were serious (Severe=4; Life-threatening=1). Median time from CAR-T therapy to bacterial infection was 70 days (range 30 - 584); 10 occurred among 99 at risk during day 30-100 (10%), 3 among 39 at risk during day 101-365 (8%), and 1 among 12 at risk after day 365 (8%). All but one of the severe or life-threatening infections occurred prior to Day 100. Characteristics and timing of individual infections are outlined in Table 3. Table 3.Characteristics and Timing of Individual Bacterial Infections Conclusion Bacterial infections were relatively uncommon in patients with late neutropenia after CD19 CAR-T therapy for NHL in the absence of antibacterial prophylaxis and most severe infections in this population occurred between day 30 and 100. Further studies are needed to inform optimal prevention strategies. Disclosures Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Scynexis: Grant/Research Support Caron Jacobson, MD, MMSc, Abintus Bio: Advisor/Consultant|Bluebird Bio: Advisor/Consultant|BMS/Celgene: Advisor/Consultant|Daiichi-Sankyo: Advisor/Consultant|Epizyme: Advisor/Consultant|ImmPACT Bio: Advisor/Consultant|Instill Bio: Advisor/Consultant|Ipsen: Advisor/Consultant|Kite/Gilead: Advisor/Consultant|Kite/Gilead: Grant/Research Support|Lonza: Advisor/Consultant|Novartis: Advisor/Consultant|Pfizer: Grant/Research Support.

Novel xeno-free and serum-free culturing condition to improve piggyBac transposon-based CD19 chimeric antigen receptor T-cell production and characteristics

Background aimsChimeric antigen receptor (CAR) T cell is a novel therapy for relapse and refractory hematologic malignancy. Characteristics of CAR T cells are associated with clinical efficacy and toxicity. The type of serum supplements used during cultivation affects the immunophenotype and function of viral-based CAR T cells. This study explores the effect of serum supplements on nonviral piggyBac transposon CAR T-cell production. MethodsPiggyBac CD19 CAR T cells were expanded in cultured conditions containing fetal bovine serum, human AB serum or xeno-free serum replacement. We evaluated the effect of different serum supplements on cell expansion, transduction efficiency, immunophenotypes and antitumor activity. ResultsXeno-free serum replacement exhibited comparable CAR surface expression, cell expansion and short-term antitumor activity compared with conventional serum supplements. However, CAR T cells cultivated with xeno-free serum replacement exhibited an increased naïve/stem cell memory population and better T-cell expansion after long-term co-culture as well as during the tumor rechallenge assay. ConclusionsOur study supports the usage of xeno-free serum replacement as an alternative source of serum supplements for piggyBac-based CAR T-cell expansion.

Treatment decision conversations, symptoms, and functional status in older adults with advanced cancer: An exploratory study utilizing mixed methods

IntroductionAdults 65 years of age or older with metastatic cancer face complicated treatment decisions. Few studies have explored the process with oncology clinicians during clinic encounters. Our exploratory study evaluated whether symptom burden or functional status impacted treatment decision conversations between older adults, caregivers, and oncology clinicians in a single National Cancer Institute within the Mountain West region. Materials and methodsWe conducted an observational, convergent mixed methods longitudinal study between November 2019 and January 2021; participants were followed for six months. The MD Anderson Symptom Inventory (MDASI) and Katz Index of Independence in Activities of Daily Living (ADL) were administered prior to clinical encounter. Ambulatory clinic encounters were audio recorded, transcribed, and analyzed. Nineteen older adults with a metastatic cancer diagnosis or a relapsed refractory hematologic malignancy were approached to achieve a sample of fifteen participants. The main outcome of interest was the number and quality of treatment decision making conversations, defined broadly and encompassing any interaction between the participant and oncology provider that involved (a) an issue or concern (e.g., symptoms, quality of life) brought up by anyone in the room during the clinical encounter, (b) a clinician addressing the concern, or (c) the patient or caregiver making a decision that involved a discussion of their goals or treatment preferences. ResultsNine men and six women with a mean age of 71.3 years (6.6; standard deviation [SD]) were enrolled, and four died while on study. Participants were followed from one to ten visits (mean 4.5; SD 2.8) over one to six months. Of the 67 analyzed encounters, seven encounter conversations (10%) were identified as involving any type of treatment decision discussion. The seven treatment decision conversations occurred with five participants, all male (although female participants made up 40% of the sample), and 63% of participants who reported severe symptoms on the MDASI were female. Severe symptoms or functional status did not impact treatment conversations. DiscussionOur results suggest that older adults with incurable cancer and their oncology clinicians do not spontaneously engage in an assessment of costs and benefits to the patient, even in the setting of palliative treatment and significant symptom burden.

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as "fourth generation" CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFNα and IFNβ CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under "stress" conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.

A qualitative service evaluation of patient and caregiver experiences of CAR-T therapy: Recommendations for service development and implications for palliative care teams

Background: Chimeric Antigen-Receptor-T-cell (CAR-T) therapy is a potentially life-saving treatment for refractory haematological malignancies. Internationally, CAR-T services are undergoing rapid development. Despite this, research on the lived experiences of patients receiving novel immunotherapies is limited. Little is known about their supportive care needs. Consequently, dedicated palliative and supportive care services may not be considered. Aim: To explore the patient and caregiver experience of CAR-T therapy and identify unmet needs to inform service development. Design: A qualitative longitudinal service evaluation. Sixteen interviews were conducted between December 2020 and March 2021 with patients (n = 10) and family caregivers (n = 4). Thematic analysis was underpinned by a constructivist approach. Setting/participants: All patients and caregivers attending one UK centre for CAR-T therapy were eligible. Semi-structured interviews were conducted at specific time points: prior to infusion, one month after infusion and follow-up post-treatment (5–18 months). Results: Identified themes described the unique challenges of CAR-T therapy. From the point of referral patients had a wide range of supportive care needs. Initially, this was attributed to prior receipt of multiple failed treatments. Subsequently, CAR-T side-effects impacted on quality-of-life and physical function. Significant psychological morbidity from prognostic uncertainty was described throughout. Patients and caregivers reported that a dedicated nurse specialist – an expert, consistent point of contact – was essential. Conclusion: Patients and caregivers would benefit from early and ongoing support from palliative care, allied-health professionals and psychology. As indications for CAR-T therapy expand, there is an urgent need for multi-centre studies incorporating patient-reported outcome data to ensure patient-centred service delivery.

Role of endothelial cells in graft-versus-host disease.

To date, the only curative treatment for high-risk or refractory hematologic malignancies non-responsive to standard chemotherapy is allogeneic hematopoietic transplantation (allo-HCT). Acute graft-versus-host disease (GVHD) is a donor T cell-mediated immunological disorder that is frequently fatal and the leading cause of non-relapse mortality (NRM) in patients post allo-HCT. The pathogenesis of acute GVHD involves recognition of minor and/or major HLA mismatched host antigens by donor T cells followed by expansion, migration and finally end-organ damage due to combination of inflammatory cytokine secretion and direct cytotoxic effects. The endothelium is a thin layer of endothelial cells (EC) that line the innermost portion of the blood vessels and a key regulator in vascular homeostasis and inflammatory responses. Endothelial cells are activated by a wide range of inflammatory mediators including bacterial products, contents released from dying/apoptotic cells and cytokines and respond by secreting cytokines/chemokines that facilitate the recruitment of innate and adaptive immune cells to the site of inflammation. Endothelial cells can also be damaged prior to transplant as well as by alloreactive donor T cells. Prolonged EC activation results in dysfunction that plays a role in multiple post-transplant complications including but not limited to veno-occlusive disease (VOD), transplant associated thrombotic microangiopathy (TA-TMA), and idiopathic pneumonia syndrome. In this mini review, we summarize the biology of endothelial cells, factors regulating EC activation and the role of ECs in inflammation and GVHD pathogenesis.