Therapy-associated Toxicities Research Articles

A 5-Year Follow-up Clinical Study of the B-cell Maturation Antigen Chimeric Antigen Receptor T-cell Therapy HDS269B in Patients with Relapsed or Refractory Multiple Myeloma.

This study aimed to report the 5-year clinical outcomes of anti-B-cell maturation antigen chimeric antigen receptor (CAR) T-cell (HDS269B) therapy in patients with relapsed/refractory multiple myeloma (RRMM), including those with poor performance status [Eastern Cooperative Oncology Group (ECOG) scores 3 to 4], and to identify factors influencing long-term outcomes. Forty-nine patients with RRMM enrolled from 2016 to 2020 received HDS269B (9 × 106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months [95% confidence interval (CI), 5.01-13.99] and 20.0 months (95% CI, 11.26-28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%-36.7%) and 34.1% (95% CI, 22.7%-51.3%), respectively. Patients with ECOG 0 to 2 had marked longer survival, with a median PFS of 11.0 months and a median OS of 41.8 months. Early minimal residual disease negativity, higher and persistent CAR T-cell expansion, and the absence of extramedullary disease were associated with better survival outcomes. No new CAR T-cell therapy-associated toxicities were observed. Importantly, ECOG scores 0 to 2, prior therapy lines <4, and CAR T-cell persistence at ≥6 months were independently associated with longer OS. HDS269B is effective and safe, especially for patients with ECOG scores 0 to 2. Early CAR T-cell intervention may improve prognosis in patients with RRMM.

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

Gastrointestinal infections and gastrointestinal haemorrhage are underestimated but serious adverse events in chimeric antigen receptor T-cell recipients: A real-world study.

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved durable response in patients with hematological malignancies, however, therapy-associated multisystem toxicities are commonly observed. Here, we systematically analyzed CAR-T-related gastrointestinal adverse events (GAEs) using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC). Among 105,087,611 reports in FAERS, 1518 CAR-T-related GAEs reports were identified. 23 GAEs (n = 281, 18.51%) were significantly overreported following CAR-T therapy compared with the full database, of which 11 GAEs (n = 156, 10.28%) were associated with gastrointestinal infections (GI), such as clostridium difficile colitis (n = 44 [2.90%], ROR = 5.55), enterovirus infection (n = 23 [1.52%], ROR = 20.02), and mucormycosis (n = 15 [0.99%], ROR = 3.09). Overall, the fatality rate of 11 GI-related AEs was 29.49%, especially mucormycosis causing substantial mortality with 60%. In addition, 4 of 23 overreported GAEs were related to haemorrhage and the mortality of gastrointestinal haemorrhage was 73.17%. Lastly, 29 death-related GAEs were identified. These findings could help clinicians early alert those rarely reported but lethal GAEs, thus reducing the risk of severe toxicities.

Abstract 4717: Small molecule modulation of PP2A selectively induces oncogenic cytotoxicity through chronic and irreversible integrated stress response

Abstract High-grade serous cancer (HGSC) is the most lethal gynecological malignancy and accounts for approximately 70% of all ovarian carcinomas. Despite recent advancements in drug discovery and a deeper understanding of the genetic mechanisms that drive HGSC oncogenesis, the mortality rate has remained stagnant over the past three decades, with a 5-year survival rate below 30%. Due to the prevalence of homologous recombination defects (HRD) in over 50% of HGSC tumors, the clinical management of patients harboring these genetic vulnerabilities has vastly relied on PARP inhibitors (PARPi). Nonetheless, about 80% of these patients ultimately relapse with refractory resistant and more aggressive disease, having no effective therapeutic alternatives currently available. Therefore, there is an urgent need for novel targeted therapies to be tailored towards the treatment of HGSC. Recently, we unveiled that 95% of HGSC tumors present with a widespread loss-of-heterozygosity in genes essential to form the tumor suppressor Protein Phosphatase 2A (PP2A) heterotrimer, second only to TP53. These deleterious alterations have been established to inhibit PP2A function, preventing it from counteracting oncogenic signatures that drive tumorigenesis. Our studies revealed that a Small Molecule Activator of PP2A (SMAP) synergizes with PARPi to induce synthetic lethality in HGSC cells while displaying favorable tolerability profiles in normal tissues. Mechanistically, SMAP activates distinct translational responses and stress signatures depending on the cellular context, driving selective oncogenic cytotoxicity through a chronic and irreversible integrated stress response (ISR), independent of PERK activation. In malignant contexts, SMAP-mediated activation of PP2A specifically drives the dephosphorylation of TFE3 to transcriptionally activate ATF4 and CHOP. Consequently, as cancer cells are incapable of activating adaptive homeostatic recovery mechanisms in response to SMAP, chronic ISR is induced, ultimately leading to cell death. Conversely, non-transformed cells leverage their intrinsic ISR plasticity to adapt, thereby restoring basal functions that allow cell survival under SMAP-mediated stress conditions. Collectively, our data highlights a new role of PP2A in HGSC and further underscore SMAP's selective cytotoxicity in cancer cells, independent of oncogenic genetic vulnerabilities or HRD profiles, by leveraging ISR plasticity and intrinsic adaptive homeostatic mechanisms. Thus, this class of PP2A modulators holds tremendous promise for broader therapeutic applications across diverse patient populations and tumor histological subtypes beyond HGSC, while mitigating standard-of-care therapy-associated toxicity. Citation Format: Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Jose Colina, Jessica Teitel, Goutham Narla, Analisa DiFeo. Small molecule modulation of PP2A selectively induces oncogenic cytotoxicity through chronic and irreversible integrated stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4717.

Adaptor Anti-P329G CAR T Cells for Modular Targeting of AML

Introduction Chimeric antigen receptor (CAR) T cell therapy has achieved promising results for treatment of B cell and plasma cell malignancies, but success has been limited in the treatment of acute myeloid leukemia (AML). Numerous antigens including CD33, CD123 or CSF1R have been proposed for AML therapy. However, clinical success of CAR T cell therapy in AML is impaired by antigen heterogeneity, therapy-associated toxicities, and antigen escape. Adaptor CAR T cells which allow sequential, transient or simultaneous targeting of multiple antigens have the potential to overcome these limitations. These adaptor CAR T cells were combined with tumor antigen-directed CAR-adaptor molecules for indirect tumor binding. We developed a modular P329G-directed CAR targeting the P329G mutation in the Fc part of tumor-targeting human IgG1 antibodies containing P329G L234A/L235A (PGLALA) mutations. These PGLALA mutations render the Fc part inactive for binding to Fc gamma receptors (FcgRs) and to the complement system, and up to now, more than 20 such Fc-silenced therapeutic antibodies including an approved T cell recruiting bispecific antibody have been clinically validated. Compared to other modular CAR T cell platforms this approach does not rely on haptens or artificial tags fused to the targeting antibody and may ease development and testing of the platform. Methods A scFv-based second generation CAR vector system was used in primary human T cells. P329G-targeting CAR T cells were combined with PGLALA-Fc-mutated antibodies targeting CD33, CD123 or CSF1R. Classical, directly binding anti-CD33 and anti-CSF1R CAR T cells have been used as positive controls, while anti-CD19 CAR T cells and untransduced T cells have been used as negative controls. Different AML (MOLM-13, OCI-AML-3, PL-21, Mv4-11, THP-1 and U-937) and an ALL cell line (NALM-6) were used as target cell lines expressing the target antigens in different intensity. Effector function of CAR T cells was also tested against primary human AML blasts derived from patients. Luciferase-based killing assays, ELISA-based and flow-based analysis were used to evaluate CAR effector functions. Results Unlike CD16-CAR T cells, which bind human IgG in a non-selective manner, anti-P329G CAR T cells revealed specific effector functions only when combined with antibodies carrying PGLALA-Fc-mutations. Anti-P329G CAR T cells alone revealed no activation. Anti-P329G CAR T cells could be specifically activated by recombinant protein when combined with antibodies targeting CD33, CD123 and CSF1R leading to upregulation of T cell activation markers. Anti-P329G CAR T cells combined with PGLALA-mutated antibodies targeting CD33, CD123 und CSF1R achieved efficient in vitro cytotoxicity against tested AML cell lines and primary human AML blasts, while antigen-negative ALL cell line NALM-6 was not killed. Remarkably, effector functions of anti-P329G CAR T cells were similar to classical CAR T cells particularly when targeting CD33. This led to specific cytokine production when anti-P329G CAR T cells were co-cultured with respective antibodies and tumor cells. P329G-CAR T cells activated by recombinant CD33, CD123 or CSF1R showed no cytokine production in the presence of an antibody which was not recognizing the respective antigen. However, by switching the antibody after 24 h of stimulation towards the tumor antigen-targeting antibody, CAR T cell activation could be again achieved by the recombinant protein. Depleting the tumor antigen-targeting antibody after 24 h of stimulation decreased the cytokine production after 48 h and 72 h despite ongoing presence of the recombinant protein. This confirms the modularity and reversibility of this adaptor CAR T cell platform. Conclusions Taken together, anti-P329G CAR T cells combined with Fc-silenced tumor antigen-targeting IgG1 antibodies carrying the clinically validated PGLALA-mutations in the Fc part achieved profound effector functions against various human AML cell lines and primary AML blasts. The modular platform has the potential to overcome recent limitations of CAR T cell therapy in AML. These results support the rational for clinical translation of this novel and modular CAR T cell platform.

First clinical experience with fractionated intracavitary radioimmunotherapy using [177Lu]Lu-6A10-Fab fragments in patients with glioblastoma: a pilot study

BackgroundFollowing resection and standard adjuvant radio- and chemotherapy, approved maintenance therapies for glioblastoma are lacking. Intracavitary radioimmunotherapy (iRIT) with 177Lu-labeled 6A10-Fab fragments targeting tumor-associated carbonic anhydrase XII and injected into the resection cavity offers a novel and promising strategy for improved tumor control.MethodsThree glioblastoma patients underwent tumor resection followed by standard radio- and chemotherapy. These patients with stable disease following completion of standard therapy underwent iRIT on compassionate grounds. After surgical implantation of a subcutaneous injection reservoir with a catheter into the resection cavity, a leakage test with [99mTc]Tc-DTPA was performed to rule out leakage into other cerebral compartments. IRIT comprised three consecutive applications over three months for each patient, with 25%, 50%, 25% of the total activity injected. A dosimetry protocol was included with blood sampling and SPECT/CT of the abdomen to calculate doses for the bone marrow and kidneys as potential organs at risk.ResultsAll three patients presented without relevant leakage after application of [99mTc]Tc-DTPA. Two patients underwent three full cycles of iRIT (592 MBq and 1228 MBq total activity). One patient showed histologically proven tumor progression after the second cycle (526 MBq total activity). No relevant therapy-associated toxicities or adverse events were observed. Dosimetry did not reveal absorbed doses above upper dose limits for organs at risk.ConclusionsIn first individual cases, iRIT with [177Lu]Lu-6A10-Fab appears to be feasible and safe, without therapy-related side effects. A confirmatory multicenter phase-I-trial was recently opened and is currently recruiting.

Adjunct Therapy with T Regulatory Cells Decreases Inflammation and Preserves the Anti-Tumor Activity of CAR T Cells.

With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can resolve inflammation and treat acute and immune-mediated lung injuries. Allogeneic, cryopreserved UCB Tregs have shown a clinical benefit in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Treg cells include a lack of plasticity under inflammatory micro-environments, no requirement for HLA matching, a long shelf life of cryopreserved cells, and immediate product availability, which makes them attractive for treating acute inflammatory syndromes. Therefore, we hypothesized that adjunct therapy with UCB Tregs may resolve the undesirable inflammation responsible for CAR T cell therapy-associated toxicity. In in vitro analysis, no interference from the addition of UCB Tregs was observed on CD19 CAR T cells' ability to kill CD19 Raji cells at different CAR T: Raji cell ratios of 8:1 (80.4% vs. 81.5%); 4:1 (62.0% vs. 66.2%); 2:1 (50.1% vs. 54.7%); and 1:1 (35.4% vs. 44.1%). In the xenogeneic B-cell lymphoma model, multiple injections of UCB Tregs were administered 3 days after CD19 CAR T cell injection, and no detrimental effect of add-on Tregs was noted on the circulating CD8+ T effector cells. The distribution of CAR T cells in multiple organs remained unaffected by the addition of the UCB Tregs. Specifically, no difference in the overall tumor burden was detected between the UCB Treg + CAR T vs. CAR T alone recipients. No tumor was detected in the liver or bone marrow in CAR T cells + UCB Tregs recipients, with a notable corresponding decrease in multiple circulating inflammatory cytokines when compared to CART alone recipients. Here we show the proof of concept for adjunct therapy with UCB Tregs to mitigate the hyper-inflammatory state induced by CAR T cells without any interference in their on-target anti-tumor activity. Administration of UCB Tregs after CAR T cells allows sufficient time for their synapse formation with tumor cells and exerts cytotoxicity, such that the UCB Tregs are diverted to interact with the antigen-presenting cells at the site of inflammation. Such a differential distribution of cells would allow for a two-pronged strategy of a UCB Treg "cooling blanket" effect and lay the groundwork for clinical study.

Mechanisms and strategies for safe chimeric antigen receptor T-cell activity control.

The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities.

Role of Antibiotic Prophylaxis and GCSF Support in Preventing Systemic Anticancer Therapy-Associated Toxicities in HIV Infected Cancer Patients: A Case Series

This is a case series report of five HIV-positive patients diagnosed with non-AIDS-defining cancer who received the combination of ART and chemotherapy. There is an increasing incidence of non-AIDS-defining cancers, such as breast cancer, lung cancer, hepatocellular carcinoma, prostate cancer, colorectal cancer, and Hodgkin’s lymphoma. The purpose of this study is to see the impact of appropriate antibiotics prophylaxis and G-CSF Support in preventing the toxicities associated with systemic anti-cancer therapy (SACT) in HIV Patients. Keywords: Human Immunodeficiency Virus, Acquired Immune Deficiency Syndrome, Anti-Retroviral Therapy, AIDS Defining Cancer, systemic anti-cancer therapy (SACT), Non-Aids Defining Cancer.

Malignancy in Ataxia Telangiectasia (A-T)

RationaleAtaxia telangiectasia (A-T) is an autosomal recessive DNA repair disorder caused by biallelic mutations in the ATM gene. Clinical features include immunodeficiency, neurodegeneration and cancer predisposition. About 25% of A-T patients will develop early onset malignancies, which are difficult to treat given hypersensitivity to radiation and radiomimetic drugs. Cancer is a leading cause of death in A-T patients. MethodsWe queried the Johns Hopkins A-T Clinical Center database for patients with a confirmed cancer diagnosis. A total of 76 out of 505 patients seen at the clinic from 1995 to the present were identified. Patients were characterized by demographics, age at cancer diagnosis, A-T phenotype (classic versus atypical), ATM mutation, type of malignancy, cancer therapy, therapy modifications, therapy-associated toxicity, and two-year event free survival. ResultsWe found 56 hematologic malignancies with an average cancer diagnosis age of 14.1 years. Among patients < 18 years of age, hematological malignancies were predominant (91%), whereas among patients >18 years old, solid tumors were common (61%). 34 (60.7%) cases were non-Hodgkin lymphoma, 15 (26.7%) leukemias with T cell predominance, and 7 (12.5%) Hodgkin's lymphomas. There were 24 solid tumors in 22 patients, with an average cancer diagnosis age of 25.3 years; 9 (38%) gastrointestinal, 7 (29%) skin, 3 (13%) breast, 2 (8%) thyroid, and 1 each lung, gynecologic and parotid cancer. We found that 76% of our malignancy cohort died of cancer or therapy complications. ConclusionsWe characterized cancers in the world's largest A-T cohort with the future goal of providing improved malignancy screening and developing research protocols for standardized treatment.

Limitations and Overcomes of CAR-NK for Cancer Immunotherapy

Adoptive cell treatment utilising chimeric antigen receptor (CAR) immunotherapy is gaining remarkable breakthroughs. In solid tumours, CAR immunotherapy lags far behind. CAR T cell production, does not have tumor-specific antigens, and is not effective in CAR T cell infiltration and trafficking into tumour sites, therapy-associated toxicity, immunosuppressive TME, and antigen escape are among the primary obstacles for CAR immunotherapy in solid tumours. Compared to CAR T cells, CAR NK cells have a number of benefits, including the ability to be processed from preexisting cell lines with mismatched MHC, the ability to kill bad cells via CAR-independent and CAR-dependent pathway with less toxicity. One clinical study demonstrated the effectiveness and safety of CAR NK cell treatment. However, CAR NK cell therapy also has its drawbacks, including, low persistence, lack of transporting pathway, immunosuppressive tumour microenvironment, and low lentivirus transduction efficiency. Solving these issues are significantly important for this technology to be accepted in future use.

Total marrow irradiation versus total body irradiation using intensity-modulated helical tomotherapy

BackgroundTotal body irradiation (TBI) is often a component of the conditioning regimen prior to hematopoietic stem cell transplantation in patients with hematological malignancies. However, total marrow irradiation (TMI) could be an alternative method for reducing radiation therapy-associated toxicity, as it specifically targets the skeleton and thus could better protect organs at risk. Here, we compared dosimetric changes in irradiation received by the target volume and organs at risk between TBI and TMI plans.Materials and methodsTheoretical TMI plans were calculated for 35 patients with various hematological malignancies who had already received TBI in our clinic. We then statistically compared irradiation doses between the new TMI plans and existing TBI plans. We examined whether TMI provides greater protection of organs at risk while maintaining the prescribed dose in the targeted skeletal area. We also compared beam-on times between TBI and TMI.ResultsTMI planning achieved significant reductions in the mean, minimum, and maximum irradiation doses in the lungs, kidneys, liver, spleen, and body (i.e., remaining tissue except organs and skeleton). In particular, the mean dose was reduced by 49% in the liver and spleen and by 55–59% in the kidneys. Moreover, TMI planning reduced the corpus beam-on time by an average of 217 s.ConclusionTMI planning achieved significant dose reduction in organs at risk while still achieving the prescribed dose in the target volume. Additionally, TMI planning reduced the beam-on time for corpus plans despite a high modulation factor.Graphical abstract

Palliative Radiotherapy for Symptomatic Locally Advanced Breast Cancer.

Objective: Women with locally advanced breast cancer (LABC) or inoperable local recurrence often suffer from a significantly reduced quality of life (QOL) due to local tumor-associated pain, bleeding, exulceration, or malodorous discharge. We aimed to further investigate the benefit of radiotherapy (RT) for symptom relief while weighing the side-effects. Materials and methods: Patients who received symptom-oriented RT for palliative therapy of their LABC or local recurrence in the Department of Radiation Oncology at Heidelberg University Hospital between 2012 and 2021 were recorded. Clinical, pathological, and therapeutic data were collected and the oncological and symptomatic responses as well as therapy-associated toxicities were analyzed. Results: We retrospectively identified 26 consecutive women who received palliative RT with a median total dose of 39 Gy or single dose of 3 Gy in 13 fractions due to (impending) exulceration, pain, local hemorrhage, and/or vascular or plexus compression. With a median follow-up of 6.5 months after initiation of RT, overall survival at 6 and 12 months was 60.0% and 31.7%, and local control was 75.0% and 47.6%, respectively. Radiation had to be discontinued in 4 patients due to oncological clinical deterioration or death. When completed as initially planned, symptom improvement was achieved in 95% and WHO level reduction of analgesics in 28.6% of patients. In 36% (16%) of patients, local RT had already been indicated >3 months (>6 months) before the actual start of RT, but was delayed or not initiated among others in favor of drug alternatives or systemic therapies. RT-associated toxicities included only low-grade side-effects (CTCAE I°-II°) with predominantly skin erythema and fatigue even in the context of re-RT. Conclusion: Palliative RT in symptomatic LABC or locoregional recurrence is an effective treatment option for controlling local symptoms with only mild toxicity. It may thus improve QOL and should be considered early in palliative patient care management.

Dynamics of Mortality and Transformation Risk within Different Risk Groups of Patients with Myelodysplastic Syndromes Stratified According to the IPSS-R - Comparison of Treated and Untreated Patients and Consequences for the Description of Risk Categories

Background In MDS, most risk assessment tools such as the IPSS-R estimate risk at time of diagnosis. Risk assigned by the IPSS-R categories, however, is not constant over time. Changes in hazard (= time specific risk in a short time interval) during course of the disease affect the use of prognostic tools and may influence clinical decisions. We have previously shown time related hazard changes in untreated patients leading to declining risk in higher risk groups and diminution of differences between risk groups over time. Aim of this study was to investigate hazard changes in patients undergoing disease-modifying treatment. Patients and methods 16 international partners of the IWG-PM contributed data from 9179 primary MDS patients of which 2015 had disease modifying treatment: median age 70.0 yrs, 60% male, median follow up 4.1 yrs, median OS 3.8 yrs, IPSS-R categories: very low 16%, low 35%, intermediate 22%, high 15%, very high 12%. Treatment modalities included hypomethylating agents, lenalidomide, cytotoxic therapy, 17% had stem cell transplantation. Time variations were described by smoothed hazard graphs and by the Cox zph test including rho, a measure for a linear time dependent impact of a feature on hazard. Semiparametric accelerated failure time models were estimated by direct optimization procedures. Results and discussion Using hazard graphs and the Cox zph-test we confirmed changes in hazard relations over time in the untreated subsample (rho -0.20 for OS). In treated patients a similar diminution was observed (rho -0.26 for OS). Results from treated patients revealed temporary increased hazard after some months especially in higher risk patients. Possible reasons are decision to start treatment when hazard increases or transient risk by therapy-associated toxicity, as well as a "guarantee time bias", induced by delayed treatment start, which in treated patients implicitly guarantees survival until start of treatment. To account for the latter, analyses were repeated excluding "guarantee time” in treated patients, again showing hazard reduction in higher risk patients and diminution between risk categories: untreated: rho -0.20 for OS, treated: rho -0.08 (fig A-B). Differently developing changes in hazards over time contradict the proportional hazards assumption of the Cox model. Therefore, as an alternative we investigated accelerated failure time models - fitting semi parametric models for IPSS-R risk categories: results show that patients in different risk categories share similar course of hazards - only at different "speeds” (speed-factors excluding guarantee time to achieve average survival: VERY LOW 0.34, LOW 0.63, INT 1.15, HIGH 2.23, VERY HIGH 5.11.) Transforming time accordingly makes common patterns visible, as in figure C, where most risk categories show hazard peaks before reaching the time of their median survival. Conclusions In MDS, hazards are not constant over time, possibly slightly rising until around the category specific median survival times and later clearly falling, except for the very high risk category. Longitudinal changes of hazards are not proportional between IPSS-R categories, instead diminution of hazard proportions between risk categories is observed. To describe the development of hazard for different IPSS-R categories the concept of different "speeds” of the disease development may be appropriate. Clinicians need to be aware of the dynamics of hazards in MDS when counselling patients both treated or those receiving supportive care only. Risk assessment at time of diagnosis by the IPSS-R assigns average group differences but changes over time need to be taken into account. Our data suggest that median survival times for IPSS-R categories approximately express different speeds and also indicate the time, when survival hazards are declining. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comorbidities Associated with Early Mortality after CD19 CAR-T Cell Therapy

Objective: CD19 chimeric antigen receptor (CAR) T-cell therapy has changed the standard for treatment of relapsed and/or refractory (r/r) large b-cell lymphoma (LBCL). Currently, pre-treatment evaluation of patients and disease factors do not accurately predict outcomes. This study aims to identify risk factors associated with early mortality prior to day 100 after CAR-T infusion. Methods: We performed a single-centered retrospective adult patients (pts) with r/r LBCL who received CAR-T cell therapy between 2018-2021. CAR-T cell toxicities graded according to either CAR T-Cell Therapy-Associated Toxicity (CARTOX) grading system prior to May, 2019 or American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading thereafter for cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Comorbidities defined as per Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). (Sorror et al., 2009). Hepatic dysfunction defined as infection with hepatitis B or C or history of liver cirrhosis or elevated total bilirubin, AST, or ALT on at least two values on two different days from day -24 till day -10 prior to CAR-T. Cardiovascular (CV) comorbidity determined by presence of coronary heart disease, congestive heart failure or reduced ejection fraction detected by echocardiogram. Psychiatric disturbance defined as presence of depression and/or anxiety requiring treatment or consultation. Patient demographics, disease characteristics and clinical outcomes summarized through descriptive statistics. Wilcoxon rank sum test used to evaluate difference in a continuous variable between patient groups. Kaplan-Meier method used to estimate time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: Two hundred and fifty patients included in analysis. Median age of 61years (range: 18-89) and 30.8% of patients were female (n=77). Histology was categorized as LBCL (65.9%) and included diffuse LBCL or high grade LBCL, transformed follicular lymphoma (26.9%), primary mediastinal b-cell lymphoma (6.4%) or follicular lymphoma (0.8%). Majority of pts received axicabtagene ciloleucel 95.6% (n=239) while 4.4% (n=11) received tisagenlecleucel and 52% (n=130) of pts received bridging therapy. CRS of any grade was 90.4% ; ICANS any grade was 57.2% while grade 3 CRS/ICANS occurred 6.4% and 38.4% respectively. Median follow-up 24.7 months (mo) (95% CI: 20.7 ~ 26.4 mo). One-hundred twenty-eight pts died during follow-up, 48 pts died within 100 days, and most common cause of death was progression of lymphoma (29.2%; n=73). Early 30-day mortality occurred in 4.8% pts and causes of death due to CAR-T related toxicity in 6 pts, disease progression in 3 pts, and infection in 1 pts. 100-day mortality rate was 24.6% (n=32) for pts >60 years old vs 13.3% (n=16) for <60 (p-value=0.02). 100-day mortality rate was 36.5% for ECOG 2-4 vs 14.9% for ECOG 0-1 (p-value=0.0005). In terms of non-relapsed mortality (NRM), risk stratification according to cumulative HCT-CI score was not associated with higher 100-day NRM (p=0.24). Pts with cardiac score of 1 had a higher NRM (26.9% vs. 8.1%; p-value=0.005). The 100-day NRM rates for hepatic score of 0, 1, and 3 were 8.9%, 14.3%, and 50% (p-value=0.04). Pts with psychiatric disturbance score of 1 had higher 100-day NRM (19.6% vs. 7.8%; p-value=0.03). Conclusion: This single center retrospective study observed an increase in 100-day mortality in correlation with pre-treatment performance status, and older age. Pts with cardiac comorbidity, hepatic dysfunction or psychiatric disturbance had a higher 100-day NRM. Similar to other studies, the combined HCT-CI score was not predictive of NRM, but individual variables were associated with higher non-CART related toxicity. These findings require validation with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Application of nanotechnology in CAR-T-cell immunotherapy

It is cellular immunotherapy for the tumor that the in vitro modified immunocytes from patients or donors are reinfused into patients to kill tumor cells. Chimeric antigen receptor T cell (CAR-T) therapy, one of the most successful and representative tumor cellular immunotherapies, is now the weapon for cancer after extensive research. Although CAR-T immunotherapy achieves success in treating relapsed/refractory hematological tumors, its drawbacks, including the poor effect in solid tumors, cytokine release syndrome (CRS) or CAR-T-related encephalopathy syndrome (CRES), on-target, off-tumor effect, and high cost, cannot be overlooked. Nanotechnology is advantageous in the construction of CARs, the transfection of T cells, the expansion, delivery, and antitumor effect of CAR-T cells, and the reduction of CAR-T therapy-associated toxicities. Currently, introducing nanotechnology into CAR-T immunotherapy has already been performed in numerous studies with highly promising results. In this review, we summarized the nanotechnologies used in CAR-T immunotherapy and discussed the challenges and directions of CAR-T immunotherapy combined with nanotechnologies in the future.

Definition of an Normal Tissue Complication Probability Model for the Inner Ear in Definitive Radiochemotherapy of Nasopharynx Carcinoma.

Simple SummaryDefinitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. In this retrospective study of 46 patients, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of <44 Gy (Dmean) or <58 Gy (Dmax) are suggested to limit the probability of inner ear toxicity < 25%.Background: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. Patients and Methods: This retrospective study investigates the inner ear toxicity of 46 patients who received radio(chemo-)therapy for nasopharyngeal carcinoma at our institution from 2004 to 2021 according to CTCAE criteria. For each inner ear, the mean and maximum dose in Gray was evaluated and correlated with clinical toxicity data. Based on the data, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. Results: In 11 patients () hearing impairment and/or tinnitus was observed as a possible therapy-associated toxicity. was between 15– Gy, whereas was between 30– Gy. There was a dose-dependent, sigmoidal relation between inner ear dose and toxicity. A of Gy and Gy was associated with inner ear damage in and of patients, respectively. The maximum curve slope (m) was found at and is . The Dmax values showed a and complication probability at Gy and Gy, respectively, and a maximum slope of the sigmoid curve at with . Conclusion: There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of Gy or Gy are suggested to limit the probability of inner ear toxicity .

Combined inhibition of BADSer99 phosphorylation and PARP ablates models of recurrent ovarian carcinoma

BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPis) have been approved for the treatment of recurrent epithelial ovarian cancer (EOC), regardless of BRCA status or homologous recombination repair deficiency. However, the low response of platinum-resistant EOC, the emergence of resistance in BRCA-deficient cancer, and therapy-associated toxicities in patients limit the clinical utility of PARPis in recurrent EOC.MethodsThe association of phosphorylated (p) BADS99 with clinicopathological parameters and survival outcomes in an EOC cohort was assessed by immunohistochemistry. The therapeutic synergy, and mechanisms thereof, between a pBADS99 inhibitor and PARPis in EOC was determined in vitro and in vivo using cell line and patient-derived models.ResultsA positive correlation between pBADS99 in EOC with higher disease stage and poorer survival is observed. Increased pBADS99 in EOC cells is significantly associated with BRCA-deficiency and decreased Cisplatin or Olaparib sensitivity. Pharmacological inhibition of pBADS99 synergizes with PARPis to enhance PARPi IC50 and decreases survival, foci formation, and growth in ex vivo culture of EOC cells and patient-derived organoids (PDOs). Combined inhibition of pBADS99 and PARP in EOC cells or PDOs enhances DNA damage but impairs PARPi stimulated DNA repair with a consequent increase in apoptosis. Inhibition of BADS99 phosphorylation synergizes with Olaparib to suppress the xenograft growth of platinum-sensitive and resistant EOC. Combined pBADS99-PARP inhibition produces a complete response in a PDX derived from a patient with metastatic and chemoresistant EOC.ConclusionsA rational and efficacious combination strategy involving combined inhibition of pBADS99 and PARP for the treatment of recurrent EOC is presented.

Patient-Reported Financial Burden Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer.

Introduction and ObjectivesIn patients with localized prostate cancer, 5-fraction, stereotactic body radiation therapy (SBRT) has been found to offer comparable oncologic outcomes and potential for improved treatment compliance compared to conventional, 40-plus fraction radiation therapy (RT). Recent studies of oncologic patient experiences have highlighted both the impact of therapy-associated financial toxicity (FT) on treatment adherence and health-related quality of life (HRQOL).MethodsA cross-sectional assessment of FT after SBRT was performed using the 12-item COST questionnaire. The total questionnaire score (range 0–44) was used to evaluate the FT grade (0–3), with a higher COST value representing lower grade. The patient zip code was used to approximate the distance from the index hospital. Univariate and multivariate analyses of the average COST score (0–4) are performed.ResultsThe response rate was 57.5% (332 of 575 consented patients) with 90.7%, 8.2%, and 1.1% experiencing grade 0, 1, and 2 FT, respectively, with no grade 3. Unemployment or disability, non-white race, low income, and concurrent hormonal therapy were associated with a statistically significant worse FT (lower COST value) on univariate and multivariate analyses (p < 0.05). Education level and insurance status significant were evaluated on univariate analysis only. There was a non-statistically significant difference in age, marital status, time since treatment, and distance from the index hospital.ConclusionsSBRT was associated with low FT. However, statistically significant socioeconomic disparities in FT remain despite ultra-hypofractionated treatment.

Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy.

Anti-epidermal growth factor receptor (EGFR) therapy-associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.