Durable Clinical Remission Research Articles

CAR T-cells in autoimmunity: game changer or stepping stone?

The advent of chimeric antigen receptor (CAR) T-cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article examines the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus (SLE), have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T-cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymph structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared to malignancies. Technological advances in cell therapy, such as next-generation CAR T-cells, allogeneic off-the-shelf products and alternative cell types such as regulatory CAR T-cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T-cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T-cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.

Immunotherapy with genetically engineered T cells holds promise for the treatment of nonmalignant diseases in the dog.

The ability to genetically redirect the antigenic specificity of T cells using chimeric antigen receptors (CAR) has led to unprecedented durable clinical remissions in human patients with relapsed/refractory hematological malignancies. This remarkable advance in successful immune cell engineering has now led to investigations into the application of CAR-T-cell technology to treat nonmalignant diseases. The use of CAR-T cells to target and eliminate specific cell subsets involved in the pathogenesis of autoimmunity, fibrosis, senescence, and infectious disease represents a new direction for adoptive cell therapies. While the use of CAR-T cells for nonmalignant disease is still in its infancy, early reports of dramatic clinical responses to CAR-T cells targeting CD19+ B cells in patients with severe autoimmune disease raise the possibility that this approach could lead to durable remissions, eliminating the need for ongoing conventional immunosuppressive therapies. Excitingly, nonmalignant disease processes that may be addressed by CAR-T-cell therapy in humans also occur in our canine populations. Given that technologies for developing canine CAR constructs are now available, robust protocols have been described for generating canine CAR-T cells, and experience is being gathered with their clinical use in oncology, it is anticipated that CAR-T cells will soon enter the veterinary clinics for the treatment of debilitating nonmalignant diseases. Here, we provide a broad overview of CAR-T-cell therapies for nonmalignant diseases and extrapolate these advances into the veterinary space, highlighting areas in which canine CAR-T cells are poised to enter the clinics for the treatment of nonmalignant disease.

DOP12 Efficacy and safety of obefazimod in UC patients at weeks 48 and 96 of an open-label maintenance study among clinical responders at week 8 of the Phase 2b induction trial

Abstract Background Obefazimod is an investigational, oral, once-daily, small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we report efficacy and safety at weeks 48 and 96 among patients who achieved clinical response at week 8 of the double-blind induction trial and compared efficacy to the overall study population. Methods Patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) during the Phase 2b, induction trial and, irrespective of their clinical response, could enter the optional 96-week OLM study with obefazimod 50mg od. Patients were followed monthly for safety and efficacy. This analysis focuses on efficacy and safety among patients who reached clinical response (decrease from baseline in the Modified Mayo score (MMS) ≥ 2 points and ≥30% from baseline, plus a decrease in rectal bleeding sub-score (RBS) ≥ 1 or an absolute RBS ≤ 1) at week 8 of double-blind induction and continued treatment in the OLM. Results Among the 217 patients who participated in the OLM, 57% (124/217) achieved clinical response at week 8 of the induction trial. Within this subgroup, 66% (82/124) and 60% (74/124) achieved clinical remission at weeks 48 and 96, respectively. Clinical response was achieved by 86% (107/124) and 77% (95/124), endoscopic improvement was achieved by 70% (87/124) and 64% (79/124), and endoscopic remission was achieved by 38% (47/124) and 42% (52/124) at weeks 48 and 96, respectively. The proportions of patients achieving these efficacy endpoints in this subpopulation were numerically higher than those observed in the overall study population (Table 1). No new safety findings were observed in this sub-population during the OLM. Conclusion A substantial proportion of patients who reached clinical response at week 8 of the induction study achieved clinical efficacy endpoints at week 48 and 96 of the open-label maintenance study. Among these patients, nearly 8 out of 10 maintained clinical response, and 6 of 10 achieved durable clinical remission for up to 96 weeks of treatment with 50 mg of once-daily obefazimod.

A phase II study of maintenance rucaparib in patients with platinum sensitive, advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2: A four year survival update.

661 Background: We previously reported the results of a single arm, phase II study of maintenance rucaparib in patients with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2 or PALB2 variants (Reiss et al, JCO, 2021). We now report the five year follow-up of this trial. Methods: Patients with advanced PC and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 were enrolled in this single arm phase II study performed at the Abramson Cancer Center. Patients were required to have received ≥16 weeks of platinum-based treatment without evidence of platinum resistance, which was defined as growing lesions, new lesions or steadily rising tumor markers. Chemotherapy was discontinued and patients received rucaparib 600mg PO BID until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: Of 42 evaluable patients, seven (16.7%) remain progression-free for over four years (5 gBRCA2, 1 sBRCA2, 1 gPALB2) of whom four (9.5%) have been progression-free for five years. Two of these four patients discontinued rucaparib due to adverse events after three and four years of therapy, respectively, without signs or symptoms of progression to date. At the cutoff date, we observe an mPFS 12.9 months, mOS 24.3 months, ORR 41.6% (9 PRs, 6 CRs), noting that three patients converted from partial to complete response since our prior publication. Two patients with ongoing responses succumbed to treatment-related MDS/AML following 2.1 and 4.8 years on study, respectively. Prior to receiving rucaparib, these individuals had received 13 and 10 months of cytotoxic chemotherapy for pancreatic cancer, respectively. Conclusions: Here we report the four year progression-free survival rate of maintenance rucaparib in patients with BRCA or PALB2 related pancreatic cancer. Our data suggest that a select portion of this patient population achieves highly durable clinical remissions. This finding is further highlighted by two patients who have discontinued rucaparib for adverse events one and two years ago, respectively, and have not had biochemical or imaging evidence of progression to date. Given the cost and risk of treatment-related leukemia associated with PARP inhibition, this data highlights the need to better understand the highly variable biology of patients with PC and BRCA or PALB2 variants, and raises the possibility of whether a very small, select group may be cured by PARP inhibitors. Clinical trial information: NCT03140670 .

Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy.

Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no clinical cancer signs for many years after treatment. However, the durable clinical benefits and long-term remissions by anti-PD-L1 monotherapy have been limited to a small fraction of patients with certain cancer types. Targeting PD-L1 via bispecific antibodies (referred to as anti-PD-L1-based bsAbs) which can simultaneously bind to both co-inhibitory and co-stimulatory molecules may increase the durable antitumor responses in patients who would not benefit from PD-L1 monotherapy. A growing number of anti-PD-L1-based bsAbs have been developed to fight against this deadly disease. This review summarizes recent advances of anti-PD-L1-based bsAbs for cancer immunotherapy in patents and literatures, and discusses their anti-tumor efficacies in vitro and in vivo. Over 50 anti-PD-L1-based bsAbs targeting both co-inhibitory and co-stimulatory molecules have been investigated in biological testing or in clinical trials since 2017. At least eleven proteins, such as CTLA-4, LAG-3, PD-1, PD-L2, TIM-3, TIGIT, CD28, CD27, OX40, CD137, and ICOS, are involved in these investigations. Twenty-two anti-PD-L1-based bsAbs are being evaluated to treat various advanced cancers in clinical trials, wherein the indications include NSCLC, SNSCLC, SCLC, PDA, MBNHL, SCCHN, UC, EC, TNBC, CC, and some other malignancies. The released data from clinical trials indicated that most of the anti-PD-L1-based bsAbs were well-tolerated and showed promising antitumor efficacy in patients with advanced solid tumors. However, since the approved and investigational bsAbs have shown much more significant adverse reactions compared to PD-L1 monospecific antibodies, anti-PD-L1-based bsAbs may be further optimized via molecular structure modification to avoid or reduce these adverse reactions.

Безопасность долгосрочного применения ритуксимаба у пациентов с ювенильным идиопатическим артритом: результаты когортного ретроспективного исследования

Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease of childhood. The goal of juvenile arthritis therapy is to achieve durable clinical and laboratory remission and a good quality of life. Various groups of drugs are used in the treatment of JIA, one of which is the anti-CD20 drug rituximab. Rituximab causes B-cell depletion, which may lead to decreased immunoglobulin levels, decreased antigen-presenting function of B-lymphocytes and impaired T-cell response. The main side effects of rituximab administration are infusion reactions, hypogammaglobulinaemia, neutropenia and infectious complications. Safety studies of rituximab use have been conducted mainly in adult patients with rheumatoid arthritis, in paediatric patients with oncological diseases and diffuse connective tissue diseases. There have been no long-term safety studies of rituximab in children with JIA. Objective. To evaluate the safety of long-term use of rituximab in patients with juvenile idiopathic arthritis. Patients and methods. A cohort retrospective study of patients with JIA aged from 2 to 17 years with evaluation of adverse events on the background of rituximab therapy was carried out; the maximum duration of follow-up was 165 months. Rituximab was administered by intravenous drip at a dose of 375 mg/m2 body surface area by 4 weekly injections (61% of all courses given) or 2 injections of 1000 mg 2 weeks apart (29%). 4% had 1 administration per course; 6% had 3 consecutive weekly administrations. The indication for repeat rituximab administration and the number of administrations were determined on an individual basis. Safety was assessed by registration of adverse events (AEs) according to medical records; AEs registered during the patient's hospitalisation and anamnestic data on AEs during the interhospital period were taken into account; infectious, infusion and other AEs were considered separately. Results. Rituximab demonstrated a sufficiently high safety profile: 88/102 (86%) patients did not report any serious AEs (grade ≥3); life-threatening AEs (grade 4-5) were reported in 7/102 (7%) patients, included 4 episodes of severe pneumonia, 3 episodes of sepsis; their incidence was 2.5 cases per 100 PY. The incidence of infectious AEs was 57.4/100 patient-years; 85% of them corresponded to mild severity; most often infectious AEs were registered in the first year of rituximab therapy; pneumonia (16/100 PY) and ENT infections (11.3/100 PY) prevailed in the structure. Infusion reactions developed with an incidence of 34.8/100 PY, most frequently registered at the first rituximab administration and manifested as influenza-like syndrome (18.4/100 PY) and rash (10.3/100 PY). The incidence of neutropenia was 17/100 PY, erythropenia 0.7/100 patient-years; decreased blood immunoglobulin levels (IgA – 5.3 episodes, IgM – 6.7, IgG – 3.4/100 patient-years), increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity – 3.9/100 PY, 1 episode of increased serum urea levels. Conclusion. The use of rituximab in patients with JIA may be accompanied by the development of AEs, which include infusion reactions, infectious complications, cytopenias, decreased level of immunoglobulins in blood, increased activity of ALT and AST. Implementation of the algorithm for the management of patients with JIA under rituximab treatment into clinical practice will allow to ensure monitoring of AEs, their detection at early stages, timely initiation of adequate therapy to prevent the development of severe complications. Key words: juvenile idiopathic arthritis, safety of therapy, rituximab, adverse events, infusion reactions, infectious complications

Durable MRD and Imaging-Negative Remission ≥ 5 Years Post-Therapy Predicts Long-Term Progression-Free Survival in Multiple Myeloma Patients - a Single-Center Observational Study

Introduction With the advent of modern multiple myeloma (MM) therapies, a significant proportion of patients can achieve durable clinical remission. Minimal residual disease (MRD) reflects depth of response and is a powerful predictor of progression-free survival (PFS) (Munshi et al, JAMA Oncology 2017). Although sustained MRD negativity (defined by IMWG as MRD-negative on two occasions, minimum one-year apart) is associated with improved PFS, there is continued long-term relapse in these patients. A recent study reported a 10-year PFS of 88% in MM patients who are MRD-negative > 3 years after total therapy (Mohan et al, Blood Advances 2022). In the current era of regular MRD testing in MM care, we aimed to estimate the 10-year PFS of unselected MM patients who are MRD and imaging-negative ≥ 5 years after latest therapy, using our single-center data. Methods MRD testing was introduced for MM patients in remission at the Icahn School of Medicine at Mount Sinai (ISMMS) in 2017. Therefore, we systematically reviewed all patients with MRD results in the ISSMS MM registry between July 2017 and December 2022. Next-generation multi-parametric flow cytometry (NGF) was used to detect MRD from 2017 to 2021, with the addition of next-generation sequencing (NGS) from 2021 onwards. MRD-negativity was defined as <1 in 10 5 by NGF or <1 in 10 6 by NGS, and one representative MRD result per year was taken for analysis. Whole-body positron emission tomography (PETCT) and MRI were used to evaluate bone or extra-medullary (EM) disease. Detailed retrospective chart review of patients with sequential MRD-negative results was conducted to identify those with durable clinical, MRD, and imaging negative remission. PFS was evaluated using Kaplan-Meier curves and survival estimates. Results Between 2017 and 2022, 1703 MM patients underwent MRD testing at our center. Of these patients, we have so far identified 92 patients who were in CR, MRD and imaging-negative ≥ 5 years after the start of latest therapy. The estimated 10-year PFS in our cohort was 91.4% (95% CI [0.833 ,1]; Figure 1). With a median follow-up time of 5.9 years (4.6 to 12.6 years), the majority of our cohort (75%) were off-therapy at last follow-up with a median time-off-therapy of 2.5 years. In terms of baseline patient and disease characteristics (Table 1), 57.6% patients were white and 60.9% were male. Most patients were ISS stage I (51.1%) with standard-risk cytogenetics (78.2%) at diagnosis. A much smaller proportion of our cohort had any adverse cytogenetics, including gain1q (13%) and del17p or TP53 mutation (7.6%). The majority of patients were in their first remission after frontline therapy (52.2%), with 33.7% having received autologous stem cell transplant (ASCT) first-line. A smaller proportion of the cohort had received salvage treatment; 31.5% had received two lines, 16.3% had received ≥ 3 lines. Four patients relapsed in this cohort (4.3%) and one patient died of a non-MM related cause. Of the patients who progressed, 2 relapsed with isolated biochemical disease and 2 with predominantly EM disease. Both biochemical relapses were preceded by conversion to MRD positivity by NGF 6 months to 1 year prior, whereas those relapsing with EM disease remained MRD negative. Three patients had been off-treatment between 1 to 4 years prior to clinical relapse and the fourth patient progressed whilst on maintenance treatment. Conclusion We report single-institution MRD data on unselected MM patients who have durable MRD and imaging-negative remission for at least 5 years from their latest line of therapy. The estimated 10-year risk of disease-progression in our cohort is around 8.6%, with the majority of patients being off-therapy. The low rate of disease-progression at 10 years demonstrates that a proportion of MM patients do not suffer multiple relapses and may therefore be potential candidates for discontinuation of maintenance. From our data, these patients are more often ISS stage I, have standard risk cytogenetics and achieve deep responses to frontline therapy. A smaller proportion of patients are able to achieve this landmark even after salvage therapies. This may be increasingly possible in the era of monoclonal antibodies and T cell redirection therapies. Analysis of larger real-world MM cohorts is needed to elucidate whether sustained MRD-negative remission at 5 years can truly predict long-term disease-free survival and possible cure.

P537 Prevalence of post-COVID-19 vaccination IBD flare-ups: a single-center prospective study.

Abstract Background Case reports of IBD flares after COVID-19 vaccination have been reported. These cases appear to be rare. In a recent study analyzing adverse event rates and impact on clinical activity of IBD after COVID-19 vaccination, the authors reported a rate of IBD reactivation in 2% of cases defined as reactivation of symptoms associated with a change in therapy (Prevent COVID Study) (Weaver et al. IBD 2022). Methods Any patient with IBD, followed as an outpatient in our department and having accepted to be vaccinated against COVID-19, was proposed this study. All the patients included in the study had to contact the department if, within one month of receiving the COVID-19 vaccine, they presented a clinical picture suggestive of an IBD relapse. The patients were reviewed in emergency and an assessment of IBD activity was made: clinical activity score, CRP and/or calprotectin dosage, short endoscopy in case of UC, colonoscopy or MRI in case of CD. The link between vaccine and relapse was defined by the absence of clinical activity for at least 3 months before vaccination and relapse of the disease at the latest within 30 days after vaccination without therapeutic modification in between. Results 231 patients (mean age: 44.6 years, sex ratio M/F=1.1, 43.3% MC) were eligible. 176 patients had at least three doses of vaccine, all with mRNA, and 55 with no more than two doses. 97 patients (42%) were infected at least once with COVID 19, confirmed by PCR after at least one dose of vaccine, all without resorting to hospitalization, resuscitation or death. 29 patients (12.5%) developed IBD after vaccination (43.6% MC, sex ratio=1, 80% of cases after 3 doses of vaccine) after a median time of 8.5 days (5-17 days). Patient characteristics, treatment received, number of vaccinations, or Covid infection were comparable between groups with and without reactivation after COVID-19 vaccine (P=NS). The risk of relapse after vaccination was 29 per 646 vaccine doses (4.4%). Table 1 reports pre-exacerbation treatments and proposed treatment changes as well as medium-term response. For IBD flares, no severe forms, hospitalization or surgery were observed. Fifteen patients were optimized on their treatment and 18 were switched to another treatment. All were put into clinical remission of their disease. In univariate analysis, no clinical parameter (type of IBD, age, sex, smoking), the number of previous vaccinations, a previous infection with covid 19 or the type of treatment was associated with a significant risk of relapse after vaccination. Conclusion The risk of IBD relapse in patients in durable clinical remission is possible after COVID-19 mRNA vaccination but remains low (4%). No risk factors were isolated in this work.

MRD Status By Clonoseq ® Is a Poor Predictor of Long-Term Outcomes after Bispecific LV20.19 CAR T-Cell Therapy for Relapsed, Refractory B-Cell NHL

INTRODUCTION: The clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) uses next-generation sequencing (NGS) based testing to identify disease-specific immunoglobulin sequences and detect evidence of minimal residual disease (MRD). MRD assessments have been shown to predict progression-free survival and overall survival in non-Hodgkin's lymphoma (NHL) patients. We report MRD results via the commercially available clonoSEQ® assay and its association with durability of response in patients treated with bispecific LV20.19 CAR in our phase 1/2 trial (NCT04186520). METHODS: We conducted a phase 1/2 single-center prospective trial (NCT04186520) to evaluate the efficacy and safety of LV20.19 CAR T-cells in patients with NHL at 2.5x106 cells/kg dose. LV20.19 CAR T-cells were manufactured onsite at varying lengths of manufacturing (8 vs 12 days) in the CliniMACS Prodigy device with IL7+15 for cell expansion, with the goal of fresh infusion. The commercial clonoSEQ® assay (by Adaptive Biotechnologies) was used to identify and track tumor clonotypes in responding patients at first assessment performed between Day 28-60. We evaluated associations between MRD status and long-term response post LV20.19 CAR-T cell therapy. Descriptive statistics were utilized for baseline characteristics. Survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via the log-rank test. RESULTS: Among the 32 patients enrolled in the trial, there were 26 responders on Day 28. Of these responders, 23 patients had clonoSEQ® B-cell MRD assay done between Day 28-60 post CAR infusion (Table 1). MRD was performed in 11 patients with Diffuse Large B-cell Lymphoma (DLBCL), 3 patients with Follicular lymphoma (FL), and 9 patients with Mantle Cell Lymphoma (MCL). The median age was 64 years (45-74) and the median lines of prior therapy were 4 (2-11). Of the 23 patients with early MRD status available, the day 28 objective response rate (ORR) was 100% (complete response=57%, n=13 and partial response=43%, n=10). Eighteen patients (78%) were MRD negative at first assessment between days 28-60 and 5 (22%) were MRD positive. Of the 5 patients who were MRD positive, 3 became MRD negative at day 90, 1 patient was non-evaluable due to a non-relapse mortality event, and the remaining patient remains positive but with decreasing MRD status at Day 90. None of the patients with MRD positivity at day 28 have relapsed to date. Among patients who achieved early MRD negativity (n=18), 7 (39%) have relapsed, and all were patients with either DLBCL or FL. No MRD-negative MCL patient has relapsed to date. The duration of response in MRD-negative patients was significantly improved in MCL patients compared to DLBCL/FL patients (Figure 1), p=0.02. Among the 7 MRD negative patients who relapsed, only 1 patient was detected to have disease relapse by MRD positivity, 2 were detected simultaneously on MRD testing and imaging, while 3 were detected by physical exam or imaging findings and did not have MRD testing. Interestingly, 1 patient had a central nervous system relapse while being MRD negative. CONCLUSION: Relapse after CAR T-cell therapy remains a significant clinical challenge. New predictors are indicated to determine which responding patients after CAR-T cell therapy are more likely to relapse. Utilizing the commercially available Adaptive clonoSEQ® assay, early MRD assessment was not predictive of long-term clinical outcomes in DLBCL and FL. MRD positive patients maintained durable remission and converted to MRD negativity, while early MRD negative patients continued to relapse. In contrast, MRD negativity post-CAR-T therapy did appear to predict durable clinical remission in MCL patients. Newer assays, including cell-free technologies, may be more informative for non-MCL histologies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Metabolic communication in the tumour-immune microenvironment.

The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour-immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses.

Emerging drugs for the treatment of inflammatory bowel disease

ABSTRACT Introduction Anti-tumor necrosis factor (TNF)-α have been the mainstay therapy for Crohn’s (CD) and ulcerative colitis (UC) for decades. With growing need for highly effective therapy, various therapeutic targets have been introduced including anti-integrins, anti-interleukin (IL) 12/23, selective anti-IL23, Janus Kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and mRNA-124 splicing agent. Areas covered The current state of available IBD therapies and those in development are reviewed, with recommendations made on positioning in clinical practice. Expert opinion Selecting and sequencing IBD therapies remains a clinical challenge. Disease phenotype, severity of symptoms, patient comorbidities, and prior drug exposure should be considered when considering therapy options. Anti-TNF remains a time-tested option that is effective in both UC and CD. The perception that newer biologics have slower onset of action is probably overestimated and providers should reconsider need for concurrent corticosteroid. JAK-inhibitors provide rapid symptom improvement in patients with moderate-severe UC. Due to safety concerns, it is recommended as a second-line therapy for UC. The goal for IBD treatment should be personalized, have rapid onset of action, induce durable clinical and endoscopic remission, and have excellent safety.

Abstract 4190: Combining dual CAR iPSC-derived immune cells with antibody for multi-antigen targeting to overcome clonal resistance in multiple myeloma

Abstract Resistance to CAR-T cell therapy through antigen loss and clonal heterogeneity is a major limiting factor in achieving durable responses, even in highly persistent cell therapies. Simultaneous targeting of multiple tumor antigens with a single therapeutic modality offers the potential to treat heterogeneous tumor populations, prevent antigen escape, and induce durable clinical remission. Here, we demonstrate the application of a unique dual-CAR approach simultaneously targeting two tumor associated antigens (TAA) for the treatment of multiple myeloma (MM) using an off-the-shelf induced pluripotent stem cell (iPSC) derived NK cell platform. The iPSC background has been functionally enhanced and can be combined with therapeutic antibodies. A CAR targeting B cell maturation antigen (BCMA), a well-defined TAA in MM, was designed utilizing a previously published high-affinity binding sequence shown to exhibit high selectivity to BCMA with enhanced recognition of low-BCMA expressing myeloma cells (Bluhm et al., Molec Ther 2018). This CAR was combined with a companion CAR targeting the pan-TAAs, MICA and MICB. The CAR binding sequence targets the conserved α3 domain of MICA/MICB, which we have previously shown to inhibit MICA/B shedding by blocking the putative cleavage site (Andrade et al., Science 2018). The designed anti-MICA/B-α3 CAR exhibits selective targeting potential against a broad range of tumor types. To determine the suitability of co-targeting BCMA and MICA/B in MM, we surveyed surface expression of BCMA and MICA/B on a variety of MM cancer cell lines and observed a complimentary pattern of co-expression compatible with a dual-CAR to broaden the targeting approach of malignant plasma cells. In a reductionist approach, dual CAR-iNK cells exhibited antigen-specific activation, degranulation and cytotoxicity against a Nalm6 target line constitutively expressing the BCMA and MICA/B. Similar trends were observed in a series of long-term cytotoxicity assays against several MM lines, consistent with antibody staining on target cells, illustrating that co-targeting of MICA/B and BCMA expands the breadth of coverage against MM. Known modulators of antigen expression were tested for their ability to provide further depth of response, and therapeutic antibodies such as anti-CD38 were tested in combination to exploit the non-cleavable CD16 and CD38KO edits in the iPSC backbone. These combinations were further tested in vivo against a disseminated model of multiple myeloma where BCMA/MICA dual CAR-iNK cells demonstrated superior tumor control relative to single-CAR controls, and TGI was augmented with the addition of Daratumamab. These data highlight the applicability of a multi-targeted approach in MM patients, whereby MM dual-CAR NK and/or T cells maintain responsiveness to malignant cells that shed or downregulate tumor antigens to evade treatment. Citation Format: Ketan Mathavan, John Reiser, Sajid Mahmood, Yijia Pan, Bryan Hancock, Robert Blum, Wen-I Yeh, Andrew Houk, Chia-Wei Chang, Tom Lee, Bobby Goulding, Jode Goodridge, Ryan Bjordahl, Bahram Valamehr, Uta Hoepken, Armin Rehm, Kai Wucherpfennig. Combining dual CAR iPSC-derived immune cells with antibody for multi-antigen targeting to overcome clonal resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4190.

IMMU-16. Next-generation CAR T-cells targeting IL13RA2 and secreting IL-15 achieve durable tumour clearance in pre-clinical model of diffuse midline glioma

T-cells engineered with a chimeric antigen receptor (CAR) to acquire tumour specificity provide a possible new treatment approach for childhood brain tumours. Durable clinical remissions have been achieved with CD19-directed CAR T-cells in refractory B-cell malignancies including control of leptomeningeal disease and parenchymal deposits. Early clinical data of CAR-T cells in adult glioblastoma and diffuse midline glioma (DMG) further support the rationale for development of CAR-T cell therapy for paediatric high-grade gliomas (pHGG) and other high-risk childhood brain tumours. IL13RA2 provides a suitable CAR target. It is expressed in the majority of pHGG including DMGs while expression is absent on normal (paediatric) brain tissue. Early results with CAR T-cell therapy for adult HGG has shown that IL13RA2 can be safely targeted, and potent anti-tumour activity is possible. However, responses are variable and ultimately transient. This is likely due to the immunosuppressive environment encountered by CAR T-cells at tumour sites which hampers persistent tumour-directed immunity. Here we develop a next generation CAR approach engineering T-cells with both a CAR and a cytokine signal which supports persistent anti-tumour immunity. We have generated novel IL13RA2-specific antibodies and used these to construct CARs. Using a functional screening approach assessing target-specific cytolytic function, T-cell proliferation and cytokine release, we selected the optimal IL13RA2-CAR design. Then, we generated a next generation CAR construct co-expressing inflammatory cytokine IL-15 with the IL13RA2-CAR. In a PDX model of DMG, T-cells transduced with IL13RA2-CARIL-15, in contrast to IL13RA2-CAR alone, induced long-term tumour clearance. Further in vitro testing of IL13RA2-CARIL-15 showed enhanced proliferation and resistance to immune-suppressive secreted factors such as TGF-β. In conclusion, co-expression of IL-15 with IL13RA2-CAR enhances CAR T-cell proliferation and in vivo persistence and achieves durable tumour clearance. IL13RA2-CARIL-15 is being translated into a phase I clinical trial for patients with DMG.

Glioblastoma: The Current State of Biology and Therapeutic Strategies.

Over the past two decades, there have been advances in surgical technologies and chemoradiation strategies for glioblastoma, yet durable remissions are rarely seen. As the biological challenges and genetic basis of glioblastoma have become more understood, new therapeutic strategies may lead to more durable clinical responses and long-term remissions. We believe specialized academic centers that form meaningful corporate partnerships to complement basic science infrastructure and use adaptive clinical trial designs will achieve more rapid translation of innovative approaches to glioblastoma. Here we outline the core biological challenges to be overcome in the management of glioblastoma.

Long-Term Outcomes With Adalimumab Therapy in Pediatric Crohn Disease: Associations With Adalimumab Exposure.

Pediatric Crohn disease (CD) treatment goals have evolved. Among children receiving adalimumab (ADA) we examined long-term durability of clinical remission, linear growth, and associations of trough concentration (TC) with biomarker, endoscopic and imaging outcomes. Single-center retrospective study. Pediatric CD activity index, C-reactive protein, fecal calprotectin, and height measured longitudinally. Discontinuation due to secondary loss of response (LOR) was assessed using Cox proportional hazards model. Associations between TC and clinical and biomarker remission, endoscopic and magnetic resonance imaging (MRI) improvements were assessed using Cox regression with time-dependent covariates. Between January 2007 and June 2018, 213 children (median age 14.1 years (interquartile range [IQR] 12.5-15.7) 65% males) initiated ADA. One hundred and seventy-four (82%) achieved clinical remission (PCDAI < 10). During 24.8 (IQR 15.6-38.4) months follow-up, 26 (15%) discontinued ADA due to LOR, and 10 (6%) due to adverse events. Being anti-tumor necrosis factor (TNF) naïve and inflammatory behavior associated with increased likelihood of clinical remission (odds ratio [OR] 2.39, P = 0.033, and 3.13, P = 0.013, respectively) and with decreased LOR (hazard ratio [HR] 0.3, P = 0.002, and HR 0.35, P = 0.01, respectively). Cumulative LOR among 135 anti-TNF naïve patients: 0%, 8%, 15% within 1, 2, 3 years, similarly durable with mono- and immunomodulator combination therapy. Among pre-/early pubertal children mean height (-0.82) normalized to -0.07. TC consistently >7.5 ug/mL was associated with durable clinical remission (HR = 17.24, P < 0.001); TC >10 ug/mL with durable biomarker remission (HR = 6.56, P < 0.001) and endoscopic (OR 10.4, P = 0.002) and MRI (OR 7.6, P = 0.001) improvements. ADA monotherapy maintains durable clinical remission. Biomarker remission, mucosal and transmural improvements were associated with greater ADA exposure.

Dual Chimeric Antigen Receptor Approach Combining Novel Tumor Targeting Strategies Circumvents Antigen Escape in Multiple Myeloma

Chimeric antigen receptor (CAR) T-cell therapy has proven highly effective in patients with hematological malignancies. However, resistance to CAR-T cell therapy arising from target protein shedding and other forms of antigen downregulation can lead to CAR-resistant disease relapse. Tumor escape may be successfully prevented through the simultaneous targeting of multiple tumor antigens. The ability to target multiple antigens with a single therapeutic modality offers the potential for anti-tumor responses, broader coverage of heterogeneous tumor populations, and the potential to prevent antigen escape, potentially inducing durable clinical remission. Multiple myeloma (MM) presents an ideal case to employ a dual-CAR approach, as BCMA-targeting cell therapies have shown impressive efficacy to date, but curative treatment remains elusive. Additionally, the oligoclonal nature of MM may contribute to antigen escape and clonal resistance. Here, we demonstrate the application of a unique dual-CAR approach simultaneously targeting two tumor associated antigens (TAA) for the treatment of MM. We further demonstrate the efficacy in an induced pluripotent stem cell (iPSC) platform, where a master engineered iPSC line is used as the starting material for mass production of off-the-shelf, dual-CAR immune effector cells.We selected B cell maturation antigen (BCMA), a well-defined TAA in MM, as the first antigen target. To develop the CAR-BCMA motif, we utilized our previously published high-affinity binding sequence shown to exhibit high selectivity to BCMA with enhanced recognition of low-BCMA expressing myeloma cells (Bluhm et al., Molec Ther 2018). As shown previously, the designed CAR-BCMA demonstrates potent and selective cellular cytotoxicity against MM (Figure 1a, left panel). BCMA has been observed to be actively cleaved from the surface of MM cells though, resulting in reduced efficacy and clinical relapse. To circumvent BCMA antigen escape, we developed a companion CAR targeting the pan-TAAs, MICA and MICB, which are expressed on MM plasma cells as well as monoclonal gammopathy of undetermined significance (MGUS) plasma cells. The CAR binding sequence targets the conserved α3 domain of MICA/MICB, which we have previously shown to inhibit MICA/B shedding and drive anti-tumor immunity (Andrade et al., Science 2018). The designed anti-MICA/B-α3 CAR exhibits selective targeting potential against an array of cancers, including the MM.1S cancer cell line (Figure 1a, right panel). To determine the suitability of co-targeting BCMA and MICA/B in MM, we surveyed surface expression patterns of BCMA and MICA/B antigens on a variety of MM cancer cell lines and observed a complimentary pattern of co-expression compatible with a dual-CAR to broaden targeting approach of malignant plasma cells (Figure 1b). Initial studies to evaluate the dual CAR approach in MM were performed by generating anti-BCMA and anti-MICA/B-α3 dual-CAR (MM dual-CAR) T-cells. MM dual-CAR T cells showed antigen-specific activation, degranulation and cytotoxicity against both antigens in an additive manner, consistent with the initial antibody staining on target cells and illustrating that co-targeting MICA/B and BCMA may increase the activity against MM (Figure 1c). Similar trends were observed in a series of cytotoxicity assays against several MM lines. Preliminary studies are ongoing in induced pluripotent stem cell (iPSC)-derived NK (iNK) cells expressing MM dual-CARs as a unique off-the-shelf cell therapy targeting both BCMA and MICA/B. Since MM dual-CAR iNK cells also express CD16, which mediates antibody-dependent cellular cytotoxicity, combination with therapeutic antibodies, such as anti-CD38 antibodies, can be deployed to target three TAAs for a complete therapeutic approach in MM. The data highlights the applicability of a multi-targeted approach in MM patients, whereby MM dual-CAR NK and/or T cells maintain responsiveness to malignant cells that shed or downregulate tumor antigens to evade treatment. [Display omitted] DisclosuresLee: Fate Therapeutics, Inc.: Current Employment. Wucherpfennig: Novartis: Research Funding; SQZ Biotech: Membership on an entity's Board of Directors or advisory committees; TScan Therapeutics: Membership on an entity's Board of Directors or advisory committees; Immunitas Therapeutics: Current holder of individual stocks in a privately-held company; Nextechinvest: Membership on an entity's Board of Directors or advisory committees; TCR2 Therapeutics: Membership on an entity's Board of Directors or advisory committees. Bjordahl: Fate Therapeutics: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment.

Idelalisib-Rituximab Results in Considerable Toxicity but Induces Durable Clinical Remissions in Patients with TP53 Disrupted B Cell Prolymphocytic Leukemia

BackgroundB-cell prolymphocytic leukaemia (B-PLL) is a rare disorder representing 1% of lymphocytic leukemias. With a median age of 69 years, pts characteristically present with B symptoms, marked lymphocytosis, cytopenias, massive splenomegaly and minimal lymphadenopathy. The largest trial of B-PLL included only 14 patients (pts) (Döhner et al, 1993). There are no randomized trials published in B-PLL. The median overall survival is 3 years. 13q14, 11q23 and 17p deletions are common by fluorescence- in-situ hybridisation (FISH) (Lens et al, 1999). TP53 mutations are noted in >50%, conferring resistance to immunochemotherapy (Dearden 2012). In the absence of international guidelines or trial data, clinicians typically employ fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine-R (BR) in TP53- intact pts with allogeneic stem cell transplant (allo-SCT) consolidation in eligible, chemotherapy-sensitive pts (Castagna et al, 2005). For TP53 -disrupted B-PLL, alemtuzumab has efficacy but is associated with serious infectious toxicity.The B-cell-receptor signaling pathway plays a critical role in CLL pathogenesis, although little is known regarding its importance in B-PLL (Bernal et al, 2001). This pathway is partly mediated by the activation of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) which is highly expressed in lymphoid cells (Herishanu et al, 2011). Idelalisib is a first-in-class, potent, oral, selective PI3Kδ inhibitor. Initial results of the first 5 pts in the compassionate use programme describe clear efficacy of idelalisib-rituximab (I-R) in TP53- disrupted B-PLL (Eyre et al, 2016). We update this series with considerably longer follow up and additional pts.Methods8 pts received I-R in a UK-wide compassionate use programme supported by Gilead. Data was retrospectively collected for adverse events (AEs), clinical and radiological responses. Rituximab (375 mg/m2) was given 2-weekly (cycle (C) 1-2) and then 4-weekly (C3-6). Idelalisib 150 mg b.d. was given continuously with dose interruption and reduction as required for toxicity and was continued in pts with response after C6 as monotherapy. Response was ascertained radiologically and clinically according to institutional practice. AEs were reported prospectively to Gilead. FISH for p53 deletion was performed in all pts. Sanger sequencing was performed in 3 pts. Standard infectious prophylaxis was routinely added at the time that the safety signal was announced.ResultsThe median age was 64.5 years (range: 57-76 years). 7 were male and 1 was female. The median time from diagnosis to first treatment was 9.5 months (range: 2-60 months). 1 pt had a prior splenectomy, but all others had small volume lymphadenopathy and splenomegaly prior to I-R. TP53 deletions by FISH were found in 7 pts. No known additional mutations were noted. Standard cytogenetics were not performed. 4 pts were treatment naïve, 1 pt received prior methylprednisolone, 1 pt BR, gemcitabine-cisplatin and alemtuzumab, 1 pt alemtuzumab and 1 pt R-CVP and then BR. 5 pts completed 6C x 28-day I-R. 3 pts stopped early: 1 pt died of an unrelated lung cancer in C2, and 2 pts stopped due to idelalisib-related grade (G) 4 colitis at C4.All 8 pts responded to I-R. The single pt who died early of lung cancer obtained a partial response. All other 7 pts obtained complete remission (CR) when assessed by examination, FBC, radiological and FISH. Of those 7 pts, only 1 progression has occurred. This pt subsequently responded to ibrutinib. 1 pt (treatment naïve) died in CR of G5 pneumonitis at 10 months on therapy. There are 5 ongoing CRs at a median of 18 months (range 17-29 months). 2 of these 5 have stopped idelalisib due to toxicity (both G3-4 colitis), 2 remain on monotherapy, and 1 has undergoing consolidation with an allo-SCT having stopped idelalisib (G3 diarrhoea). The median follow up for all pts is 18 months (range 1-29 months).ConclusionsI-R displays rapid, deep and durable remissions in TP53 -disrupted B-PLL. The toxicity profile of idelalisib is well described and is clearly demonstrated in this cohort. Pneumonitis, colitis and CMV reactivation were particularly noteworthy. Of interest, remissions were durable in the 2 pts that stopped therapy following colitis for 13 and 14 months respectively. Our data supports importance of compassionate use programme to study novel agents in rare disorders. Updated response and toxicity data will be presented. [Display omitted] DisclosuresFox:Gilead: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau. Bloor:Roche: Honoraria; Gilead: Consultancy, Other: travel expenses; AbbVie: Honoraria, Other: travel expenses; Janssen: Other: travel expenses, Speakers Bureau. Dungawalla:Gilead: Honoraria. Shankara:Gilead: Honoraria, Other: Travel expenses, Speakers Bureau. Schuh:Abbvie: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

P547 Safety and efficacy of vedolizumab in the treatment of patients with moderate to severe Ulcerative Colitis: a systematic review and meta-analysis

Abstract Background To perform a systematic review and meta-analysis discussing the efficacy and safety of vedolizumab (VDZ) treatment in patients with active moderate to severe ulcerative colitis (UC). Methods Using relevant keywords, we searched PubMed, Web of Science, Scopus, and Cochrane Central databases, until June 2020. We included interventional and observational cohort studies which assessed the safety and effectiveness of VDZ 300 mg intravenous infusion, in patients with active moderate to severe UC. We used the Cochrane risk of bias assessment tool and the Newcastle-Ottawa scale to assess the quality of included interventional and cohort studies, respectively. Dichotomous outcomes were pooled as proportion, 95% Confidence interval (CI), and p-value under the random-effects model in the open meta-analyst software. Results We found 10 interventional studies and 35 cohort studies, including 4,794 patients eligible for our review. Most of the included citations were single-arm studies. Our meta-analysis showed that VDZ therapy could induce a significant clinical response in UC patients up to 54 weeks (proportion 0.516, 95% CI [0.453, 0.578], p &amp;lt; 0.001). VDZ was associated with clinically significantly clinical remission and steroid-free clinical remission after 54 weeks (p &amp;lt; 0.0001). Durable clinical remission, histological remission, and endoscopic response rates were maintained in UC patients taking VDZ at the 52nd week. There was no significant difference between VDZ and placebo regarding the incidence of drug-related serious adverse events (p = 0.113) and death rates (p = 0.085). Conclusion Our systematic review and meta-analysis showed that the use of VDZ in patients with active moderate to severe UC was associated with high percentages of clinical response and remission rates in induction and maintenance treatment stages. VDZ seems to be well tolerated in UC patients, apart from some infections and inflammations. Future RCTs should compare VDZ to active treatments for longer follow-up periods with larger sample size.

T-DM1 for advanced breast cancer after multi-anti-HER2-target therapy: a case report

: We report a case of human epidermal growth factor receptor 2 positive (HER2+) breast cancer progressing to multiple metastases during several lines of anti-Her2 targeted therapy and chemotherapy, showing responses to TDM-1 and receiving clinical complete remission. The patient was diagnosed with HER2+ stage IIA invasive carcinoma of the left breast. The tumor progressed with skin invasion after neoadjuvant chemotherapy and continued progressing with sternum metastasis after trastuzumab-contained salvage treatment and dual-targeted therapy combined with chemotherapy. Afterward, the next-generation sequencing (NGS) test detected a PIK3CA mutation and the amplification of ERBB2. A third-line salvage therapy using everolimus and trastuzumab combined with chemotherapy consequently resulted in stable disease. After the therapy of TDM-1, the tumor received a durable complete clinical remission (cCR) that was maintained for 30 months. The regimen was initially TDM1 once 3 weeks for 19 months, then modified to once 4 weeks after the cCR statement lasted for 1year, and discontinued after another 10 months. During the medication, the patient regularly underwent the PET-CT every 3 to 4 months and was still disease-free until this report. This case delivers a view that keeping anti-HER2 therapy and adjusting regimens precisely according to gene sequencing can bring advanced HER2+ breast cancer to cCR.

Efficacy and safety of vedolizumab in Crohn's disease in patients from Asian countries in the GEMINI 2 study.

Background/Aims The efficacy and safety of vedolizumab in moderate-to-severely active Crohn’s disease (CD) were demonstrated in the GEMINI 2 study (NCT00783692). This post-hoc exploratory analysis aimed to assess the efficacy and safety of vedolizumab in the subgroup of patients from Asian countries.Methods During the induction phase (doses at day 1, 15), clinical remission, enhanced clinical response, and change in C-reactive protein at 6 weeks; during the maintenance phase, clinical remission, enhanced clinical response, glucocorticoid-free remission and durable clinical remission at 52 weeks, were the efficacy outcomes of interest. Efficacy and safety of vedolizumab compared to placebo were assessed in Asian countries (Hong Kong, India, Malaysia, Singapore, South Korea, and Taiwan) using descriptive analyses.Results During the induction phase, in Asian countries (n = 51), 14.7% of the vedolizumab-treated patients achieved clinical remission at week 6 compared to none with placebo (difference, 14.7%; 95% confidence interval, 15.8%–43.5%). In non-Asian countries (n = 317), the remission rate at week 6 with vedolizumab was 14.5%. During maintenance, in Asian countries, clinical remission rates at 52 weeks with vedolizumab administered every 4 weeks, vedolizumab administered every 8 weeks and placebo were 41.7%, 36.4%, and 0%, respectively; while enhanced clinical response rates were 41.7%, 63.6%, and 42.9%, respectively. During induction, 39.7% of patients with vedolizumab experienced an adverse event compared to 58.8% of patients with placebo, and vedolizumab was generally well-tolerated.Conclusions This post-hoc analysis demonstrates the treatment effect and safety of vedolizumab in moderate-to-severely active CD in patients from Asian countries.