Citations

BACKGROUND: Chimeric antigen receptor T-cell therapies (CAR-T) are transforming the treatment of B-cell leukemias and lymphomas. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome represent common, potentially life-threatening toxicities from chimeric antigen receptor T-cell therapy treatment. CASE SUMMARY: We present a 53-year-old patient with primary refractory high-grade B-cell lymphoma who developed severe, refractory neurotoxicity following chimeric antigen receptor T-cell therapy but exhibited complete recovery after extracorporeal blood purification with CytoSorb (CytoSorbents, Monmouth Junction, NJ). Six days after chimeric antigen receptor T-cell therapy infusion, the patient developed cytokine release syndrome grade 3, prompting administration of dexamethasone and tocilizumab, a monoclonal antibody against the interleukin-6 receptor. His C-reactive protein levels started to decrease with tocilizumab and dexamethasone treatments. However, his ferritin levels continued to rise, and his interleukin-6 levels were above the upper detection threshold. Thirty-six hours later, the patient showed improved cytokine release syndrome but developed severe immune effector cell-associated neurotoxicity syndrome with predominant encephalopathy (grade 3) despite treatment with dexamethasone/methylprednisolone, tocilizumab, and anakinra. We therefore sought a rescue strategy to remove inflammatory mediators. Following emergency use authorization, we initiated extracorporeal blood purification with CytoSorb (CytoSorbents). Four-day extracorporeal blood purification resulted in complete resolution of immune effector cell-associated neurotoxicity syndrome and greater than 95% reduction in interleukin-6 levels without side effects. The patient was discharged home 10 days later with no signs of neurotoxicity or other secondary end-organ dysfunction. CONCLUSIONS: Our case represents the first reported, successful application of extracorporeal blood purification with CytoSorb (CytoSorbents) to treat severe, refractory neurotoxicity following chimeric antigen receptor T-cell therapy.

Significance Statement Renal artery stenosis (RAS) engenders stenotic-kidney ischemia, dysfunction, and injury, but whether these are mediated by cellular senescence has not been elucidated. INK-ATTAC transgenic mice, high-resolution imaging, and unbiased single-cell RNA sequencing of murine kidneys demonstrated cellular senescence as an important mechanism of progressive injury to epithelial/stromal cells within poststenotic kidneys. Both p16-specific and broad quercetin/dasatinib interventions to blunt senescence improved renal function and structure, underscoring the central role of senescence in the pathogenesis. Furthermore, this mechanism was conserved in human subjects with RAS. These observations reveal new mechanisms that contribute to the pathogenesis of chronic ischemic renal injury, and support the development of senolytic therapy to reduce senescent cell burden and delay renal injury. Background Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. Methods Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function ( in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. Results Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16 Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 ( Cdkn1a ) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. Conclusions Maladaptive tubular cell senescence, involving upregulated p16 ( Cdkn2a ), p19 ( Cdkn2d ), and p21 ( Cdkn1a ) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Abstract Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. Significance: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistant-related MET amplification. This article is highlighted in the In This Issue feature, p. 2659

8023 Background: MGTA-145 (GroβT), a CXCR2 agonist, has shown promising activity for HSC mobilization with plerixafor in pre-clinical models and healthy volunteers. Methods: This phase 2 single center study evaluates HSC mobilization with MGTA-145 + plerixafor and same day apheresis in patients with multiple myeloma. Patients received plerixafor 0.24 mg/kg (0.16 mg/kg if renal dysfunction) SQ, followed 2 hours later by MGTA-145 (0.03 mg/kg) IV over 3-10 minutes and apheresis within 30 minutes. Mobilization was repeated for a second day if day 1 yield was < 6 x 106 CD34+ cells/kg. This interim analysis reports on mobilization in 10 patients (of 25 planned), including safety cohort of first 6 patients completing transplant. Primary endpoint is collection of 2 x 106 CD34+ cells/kg. Results: Median age was 63 years (range: 46-68), 50% were female, 22% had ISS stage 3 & 50% had high-risk FISH. Induction therapy was VRD in 7 and daratumumab + VRD in 3 patients; median induction duration: 4 months (3-6) & median lenalidomide exposure: 6 cycles (4-6), with > VGPR in 70%. Median total stem cell yield (CD34+ cells/kg x 106) was 7.1 (3-16.2), day 1 yield was 5.4 (1.1-16.2) & yield per apheresis session was 4 (1.1-16.2). 100% of patients met the primary endpoint of collecting sufficient HSCs in < 2 days of mobilization + apheresis to proceed to transplant (2 x 106 CD34+ cells/kg). Secondary endpoints of 4 and 6 x 106 CD34+ cells/kg in < 2 days were met in 90% & 80% patients. 30% patients underwent 1 apheresis, while 70% underwent 2 sessions. MGTA-145 was well tolerated. At least 1 adverse event (AE) was seen in 90% of patients, 20% had grade 2 AEs (anemia, hypokalemia) and 20% had grade 3 AEs (worsening of baseline grade 3 anemia; hypocalcemia); all resolved. Acute & transient bone pain was seen in 40% of patients (back-2, hip-1, sternum-1), all grade 1, all on day 1, & resolved without intervention after 6 minutes (3-10). All 6 patients in the safety cohort have completed transplant with melphalan 200 mg/m2. Median of 4.1 (3.4-5.6) x 106 CD34+ cells/kg were infused. All patients have engrafted timely (DiPersio Blood 2009); median time to neutrophil engraftment: 12 days (11-13) & platelet engraftment: 17 days (16-19). Apheresis graft analysis is available in these 6 patients. Grafts with MGTA-145+plerixafor showed high enrichment for CD90+CD45RA- among CD34+ cells, a CD34 subset of long term engrafting HSCs (median: 31% of CD34+ cells, 27-52), higher than seen with G-CSF (6%, Goncalves TCT 2021). 67% of grafts were minimal residual disease negative with next generation flow cytometry. Conclusions: This is the first study to evaluate the novel regimen of MGTA-145 + plerixafor for same day stem cell mobilization & collection in myeloma/hematologic malignancies, with 100% efficacy in interim analysis and the first to demonstrate successful engraftment in patients with cells collected with this GCSF free regimen. Clinical trial information: NCT04552743.

TPS4165 Background: Oncogenic activation of FGFR2 via genomic rearrangement, gene amplification, or point mutation in advanced solid tumors provides the opportunity for rapid clinical development of highly selective FGFR2 inhibitors using a precision oncology approach to deliver clinical benefit to genomically-defined patient (pt) populations. Unfortunately, this opportunity remains largely unrealized as current, non-selective small molecule inhibitors (pan-FGFRi) suffer from off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance leading to only modest efficacy primarily limited to FGFR2-fusion+ intrahepatic cholangiocarcinoma (ICC). RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFRi by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. We initiated a first-in-human (FIH) precision oncology study of RLY-4008 in advanced solid tumor pts with FGFR2 alterations with primary objectives to define the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) and adverse event (AE) profile of RLY-4008 and key secondary objectives to assess FGFR2 genotype in blood and tumor tissue, pharmacokinetics (PK), and anti-tumor activity. Methods: This is a global, multi-center, FIH dose escalation/expansion study of RLY-4008 (NCT04526106) in adult pts who have unresectable or metastatic solid tumors with FGFR2 alteration per local assessment, ECOG performance status 0-2, measurable or evaluable disease per RECIST 1.1, and who are refractory, intolerant, or declined standard therapy including pan-FGFRi. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. For the dose escalation (Ñ50), RLY-4008 is administered QD/BID on a continuous schedule with 4-week cycles according to a Bayesian Optimal Interval design that allows accelerated dose titration, additional accrual to dose levels declared tolerable, and exploration of alternative schedules if warranted. The MTD is determined via logistic regression of the dose limiting toxicity rate across all dose levels and an RP2D less than the MTD may be considered based on observed AEs, PK, and anti-tumor activity. Following dose escalation, the dose expansion (Ñ75) will treat pts with RLY-4008 at the MTD/RP2D and includes 5 groups with any prior therapy (except group 2): 1. FGFR2 fusion+ ICC pts; 2. FGFR2 fusion+ ICC pts with no prior FGFRi; 3. FGFR2 fusion+ pts with other solid tumors; 4. FGFR2-mutation+ solid tumor pts and 5. FGFR2-amplified solid tumor pts. The primary endpoints are MTD/RP2D and AE profile; key secondary endpoints are FGFR2 genotype in blood and tumor tissue, PK parameters; overall response rate, and duration of response per RECIST 1.1. US enrollment began SEP2020 and Europe/Asia start-up is underway. Clinical trial information: NCT04526106.