Multiple Hematologic Malignancies Research Articles

Current and emerging pharmacotherapies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis-like syndrome due to CAR T cell therapy.

Chimeric antigen receptor (CAR) T cells have revolutionized treatment of multiple hematologic malignancies. Engineered cellular therapies now offer similar hope to transform management of solid tumors and autoimmune disease. However, toxicities can be serious and often require hospitalization. We review the two chief toxicities of CAR T therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and the rarer immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. We discuss treatment paradigms and promising future pharmacologic strategies. Literature and therapies reviewed were identified by PubMed search, cited references therein, and review of registered trials. Management of CRS and ICANS has improved, aided by consensus definitions and guidelines that facilitate recognition and timely intervention. Further data will define optimal timing of tocilizumab and corticosteroids, current foundations of management. Pathophysiologic understanding has inspired off-label use of IL-1 receptor antagonism, IFNγ and IL-6 neutralizing antibodies, and janus kinase inhibitors, with data emerging from ongoing clinical trials. Further strategies to reduce toxicities include novel pharmacologic targets and safety features engineered into CAR T cells themselves. As these potentially curative therapies are used earlier in oncologic therapy and even in non-oncologic indications, effective accessible strategies to manage toxicities are critical.

Abstract LB126: Generation of a novel ROR1 x CD3 bispecific T-cell engager for better tumor killing and minimal cytokine release

Abstract Receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression is a highly specific tumor associated antigen expressed in multiple hematological malignancies and solid tumors. EMB-07 is a novel monovalent asymmetrical tandem Fab (MAT-Fab) antibody composed of two different Fab fragments targeting ROR1 and CD3ε respectively, and a “knob-in-hole” Fc fragment maintaining FcRn binding and Ig-like pharmacokinetics in vivo. To avoid light chain miss-pairing, the anti-ROR1 light chain was directly connected to the N-terminus of the anti-CD3 heavy chain. The ROR1 binding arm has a high affinity of 0.52 nM and recognizes a membrane distal epitope, which is different from a reference BiTE molecule currently in clinical trial. In comparison with this BiTE molecule, EMB-07 showed similar tumor killing efficacy to ROR1 expressing tumor cell lines while it induced much lower levels of cytokines both in vitro and in vivo. Moreover, comparing with a clinical stage ROR1-vc-MMAE ADC, EMB-07 demonstrated ~500-fold increased tumor lysis potency in vitro. In PD-1 resistant tumor xenograft mice models, EMB-07 showed potent tumor growth inhibition and synergistic activity in combination with PD-1 blockade. In a preclinical GLP toxicological study, EMB-07 was well tolerated in cynomolgus monkeys with no evidence of lethality, life-threatening toxicity, or obvious EMB-07-related macroscopic and histopathological adverse findings up to 50 mg/kg. By using a highly specific IHC clone, we validated membrane-associated ROR1 expression in multiple tumor types, including triple negative breast cancer, ovarian cancer, endometrial cancer, lung adenocarcinoma, and pancreatic cancer, while the observation of its expression in normal tissues is very limited. This study supports the clinical development of EMB-07 for treating multiple solid tumors with ROR1 expression. A FIH study of EMB-07 in locally advanced/metastatic solid tumors or relapse/refractory lymphoma is currently ongoing (NCT05607498). Citation Format: Danqing Wu, Shiyong Gong, Xuan Wu, Gaowa Naren, Liqin Dong, Stephan Lensky, Chengbin Wu. Generation of a novel ROR1 x CD3 bispecific T-cell engager for better tumor killing and minimal cytokine release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB126.

Measurement of the major ignored burden of multiple myeloma, pernicious anaemia and of other haematological conditions on partners and family members: A cross-sectional study.

Having a haematological condition can adversely affect the quality of life (QoL) of family members/partners of patients. It is important to measure this often ignored burden in order to implement appropriate supportive interventions. To measure current impact of haematological conditions on the QoL of family members/partners of patients, using the Family Reported Outcome Measure-16 (FROM-16). A cross-sectional study, recruited online through patient support groups, involved UK family members/partners of people with haematological conditions completing the FROM-16. 183 family members/partners (mean age = 60.5 years, SD = 13.2; females = 62.8%) of patients (mean age = 64.1, SD = 12.8; females = 46.4%) with 12 haematological conditions completed the FROM-16. The FROM-16 mean total score was 14.0 (SD = 7.2), meaning 'a moderate effect on QoL'. The mean FROM-16 scores of family members of people with multiple myeloma (mean = 15.8, SD = 6.3, n = 99) and other haematological malignancies (mean = 13.9, SD = 7.8, n = 29) were higher than of people with pernicious anaemia (mean = 10.7, SD = 7.5, n = 47) and other non-malignant conditions (mean = 11, SD = 7.4, n = 56, p < .01). Over one third (36.1%, n = 183) of family members experienced a 'very large effect' (FROM-16 score>16) on their quality of life. Haematological conditions, in particular those of malignant type, impact the QoL of family members/partners of patients. Healthcare professionals can now, using FROM-16, identify those most affected and should consider how to provide appropriate holistic support within routine practice.

Eosinophilia During Lenalidomide Therapy in Myelodysplastic Syndrome

BackgroundLenalidomide is an immunomodulatory therapy used to treat multiple hematologic malignancies. The incidence of eosinophilia and hypereosinophilia during lenalidomide therapy, and the requirement for high-dose steroids are not well-defined Patients and MethodsWe retrospectively reviewed 44 patients with myelodysplastic syndromes who were treated with lenalidomide therapy from August 2006 and March 2023. ResultsEosinophilia (0.5-1.5 × 109/L) and hypereosinophilia (>1.5 × 109/L) were observed in 6 patients (14%) and 4 patients (9%), respectively. The median duration of lenalidomide therapy was 6.5 months. Backward multivariate ordinary logistic regression identified higher absolute eosinophil count (OR, 4759.986; 95% CI, 11.223-2018772.073; P = .006) and longer duration of lenalidomide therapy (OR, 1.148; 95% CI, 1.012-1.302; P = .032) as independent prognostic factors for the incidence of eosinophilia and hypereosinophilia. There was a trend for a higher use of high-dose steroids with hypereosinophilia. The median time to develop the first occurrence hypereosinophilia was 0.5 months. Steroids were used in 40% of patients with eosinophilia or hypereosinophilia. All events resolved with discontinuation of lenalidomide and/or use of steroids. No long-tern lasting adverse effects were recorded. ConclusionLenalidomide may induce or worsen existing eosinophilia which may lead to the need for steroids within a month of therapy.

Abstract 3129: BYON4413, an in vivo active CD123-targeting antibody-drug conjugate, combines effectively with azacitidine and venetoclax in acute myeloid leukemia cell lines

Abstract Background: CD123, the alpha chain of the interleukin-3 receptor (IL-3Rα), is overexpressed in multiple hematologic malignancies and found particularly highly expressed on the surface of acute myeloid leukemia (AML) cells. Furthermore, increased CD123 expression on leukemic stem cells relative to non-neoplastic hematopoietic stem cells makes CD123 an attractive tumor-associated target for an antibody-drug conjugate (ADC). BYON4413 is an ADC that consists of a novel humanized IgG1 anti-CD123 antibody site-specifically conjugated with Byondis' proprietary duocarmazine linker-drug technology, ByonZine® and ByonShieLD®. The efficacy of BYON4413 is studied as monotherapy and in combination with azacitidine and venetoclax (AZA/VEN), since the AZA/VEN regimen is the standard of care (SOC) for AML patients who are ineligible for intensive chemotherapy. Method: A panel of CD123+ and CD123- hematological cell lines and AML patient-derived bone marrow mononuclear cells (BMMCs)/peripheral blood mononuclear cells (PBMCs) were utilized in in vitro studies to determine the cytotoxic effects of BYON4413. The induction of apoptosis and cell killing by BYON4413 in a triple combination with AZA/VEN was studied in vitro using the CD123+ AML cell lines MOLM-13 and MV4-11. AML patient and cell line-derived xenograft models were used to investigate the in vivo efficacy of BYON4413. Results: In vitro studies with human AML cell lines show that BYON4413 is highly effective in eradicating CD123+ cells while having little impact on CD123- cells. These results were confirmed ex vivo with AML patient-derived BMMCs/PBMCs. BYON4413 effectively killed AML patient-derived blasts while largely sparing healthy hematopoietic cells. The triple combination of BYON4413 with AZA/VEN enhanced both apoptosis and cell killing of AML cell lines compared to the singular BYON4413 treatment. In vivo studies demonstrate that BYON4413 is remarkably efficient at reducing the tumor burden in AML patient- and cell line-derived xenograft models. Conclusions: Preclinical studies show that BYON4413 has potential to be an effective targeted therapy against CD123+ hematological malignancies such as AML. The enhanced efficacy of BYON4413 together with AZA/VEN suggests that a clinical benefit from the triple combination may be achievable and is worth further exploration. A first-in-human dose-escalation and expansion trial with BYON4413, designed to enroll R/R AML and high-risk MDS patients, is scheduled to start in Q2 2024. Citation Format: Miranda M.C. van der Lee, Tanja van Achterberg, Kaylee Hersmus, Annet Brouwers-Vos, Monique van der Vleuten, Maurien Pruis, Wendy Kappers, Gijs Verheijden, Gerwin Huls, Glenn van Wigcheren, Ruud Ubink, Aloys Sesink, Alyson MacInnes, Jan Jacob Schuringa, Wim Dokter. BYON4413, an in vivo active CD123-targeting antibody-drug conjugate, combines effectively with azacitidine and venetoclax in acute myeloid leukemia cell lines [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 3129.

Abstract 5640: Unlocking the therapeutic potential of SF3B1 inhibitors for bladder cancer treatment

Abstract RNA splicing dysregulation is a hallmark of cancer, occurring in multiple solid and hematological malignancies. Splicing factor 3 subunit B1 (SF3B1), a key component of the U2 small nuclear ribonucleoprotein (snRNP) complex that regulates RNA splicing, is frequently altered in a variety of cancer types, including non-muscle-invasive and muscle-invasive bladder cancer, where the E902K mutation is common. In this study, we investigated the therapeutic potential of the SF3B1 inhibitor, pladienolide B, in bladder cancer using in vitro models. We used a recombinant plasmid containing the SF3B1E902K mutation and established an UMUC3E902K mutant urothelial cell line. Both UMUC3WT and UMUC3E902K cells were treated with pladienolide B alone or in combination with cisplatin to evaluate differences in cell viability. Flow cytometry using annexin V staining and propidium iodide exclusion was utilized to assess the cell death mechanism. RNAseq was performed after RNA extraction from UMUC3WT, UMUC3E902K, RT4, and HT1376 bladder cancer cell lines were treated with pladienolide alone or combined with cisplatin. We determined that the IC50 for pladienolide B is 5nM for UMUC3 cells observed 72 hours post-treatment. Treatment with pladienolide B halted the cell cycle and caused cell death by apoptosis for both UMUC3WT and UMUC3E902K cell lines. We also observed that UMUC3E902K cells were significantly more sensitive to pladienolide B compared to UMUC3WT cells (p≤0.05). Furthermore, there was a synergistic effect observed after co-treatment with low-dose pladienolide B (2 nM) and cisplatin (3 µM) for both UMUC3WT and UMUC3E902K cell lines, with UMUC3E902K cells showing greater sensitivity to combination treatment. Our results provide insights into the potential use of splicing inhibitors, alone or in combination with chemotherapy, for treating bladder cancer, specifically for tumors that bear driver mutations in splicing factors. Currently, we are evaluating the mechanism by which SF3B1 mutations make cells sensitive to pladienolide B in vitro and in vivo, with the goal of identifying specific mRNA splicing vulnerabilities that can be targeted by anti-sense or splice-switching oligonucleotides to achieve anti-tumor outcomes. Additional differential splicing patterns and preliminary in vivo results will be presented. Citation Format: Rod Carlo Columbres, Arup Chakraborty, Andrea Apolo, Rouf Banday. Unlocking the therapeutic potential of SF3B1 inhibitors for bladder cancer treatment [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 5640.

Acalabrutinib-Related Dermal Toxicities: A Next-Generation Diagnostic Challenge

Abstract Introduction/Objective Bruton's tyrosine kinase (BTK) inhibitors represent an advance in treating multiple hematologic malignancies. Next-generation BTK inhibitors, acalabrutinib, have been designed to optimize BTK inhibition and decrease the potential of associated side effects. Methods/Case Report A 74-year-old male presented with generalized weakness and shortness of breath. Radiological examination revealed bilateral pleural effusions, lymphadenopathy, and hepatosplenomegaly. Evaluation of the pleural fluid showed a low-grade lymphoma. A lymph node and bone marrow biopsy revealed B-cell lymphoma with lymphoplasmacytic differentiation, with bone marrow involvement. MYD 88 mutation was identified, and it was consistent with Waldenstrom's macroglobulinemia. Acalabrutinib therapy was started, with good response. Two weeks later, he presented with two distinct rashes. 1)Blanching erythematous macules and papules coalescing to patches on the upper thighs and hypogastric region. Punch biopsy of this rash showed superficial perivascular dermatitis with predominantly T-cells and mild lobular panniculitis consistent with BTK inhibitor toxicity. 2)Red-brown erythematous plaques with induration on the central chest. The biopsy of this rash showed cutaneous involvement by the known B- cell lymphoplasmacytic lymphoma. Results (if a Case Study enter NA) NA Conclusion Cutaneous involvement by Waldenstrom Macroglobulinemia is uncommon. It can be due to 1) nonspecific rashes secondary to the hyperviscosity or cryoglobulinemia 2) cutaneous involvement by the lymphoma, called cutaneous macroglobulinosis. We present uncommon simultaneous cutaneous involvement of Waldenstrom’s Macroglobulinemia and BTK inhibitor toxicity. BTK-inhibitors-induced rashes present with a relatively non-specific and varied clinical presentation, often in chronically ill patients taking additional medications. Next-generation BTK inhibitors present a more selective binding to BTK. However, they are still associated with similar dermatological toxicities. A high index of suspicion is needed for diagnosis and treatment.

Covalent Menin Inhibitor Bmf-219 in Patients with Relapsed or Refractory (R/R) Acute Leukemia (AL): Preliminary Phase 1 Data from the Covalent-101 Study

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

Real-World Incidence, Characteristics and Management of Cytokine Release Syndrome Induced By Chimeric Antigen Receptor T-Cell Therapy across Hematologic Malignancies

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. CRS occurs with varying frequency and severity, depending on the underlying disease and immunotherapy used, such as chimeric antigen receptor T-cell (CAR-T) therapy or off-the-shelf T-cell engaging bispecific antibodies. Limited research exists on the diagnosis and management of CRS in the real world. This study describes the real-world incidence, severity and clinical management of CRS induced by commercially available CAR-T therapies for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and multiple myeloma (MM). Methods: Real-world data (RWD) were obtained from the Flatiron Health, US, nationwide electronic health record (EHR)-derived, de-identified database of cancer patients within a network comprised primarily of community cancer practices. The Flatiron Health network also includes practices designated as academic sites by the National Cancer Institute; however, relative proportions of community/academic practices may vary depending on the study cohort. Data as of August 31, 2022, on CAR-T therapy, clinical characteristics and disease outcomes specific to CAR-T therapy, as well as CRS and its clinical management, were abstracted from unstructured documents in EHRs (in addition to routinely available structured data), in a cohort of patients receiving commercial CAR-T therapy. Specifically, data for CRS including treatments and resolution were abstracted based on explicit mention of and attribution to CRS in charts. Results: Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (&amp;lt;15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL. Highest incidence of Grade ≥2 CRS was observed among MCL patients, whereas Grade ≥3 CRS was most commonly observed among FL patients. Time to onset of CRS ranged from 0 to 16 days, with median onset between 3-4 days among lymphoma patients and earlier median onset of 1 day for MM patients. Median time to CRS resolution ranged from 2 to 6 days across indications. While 81-95% of patients received CAR-T therapy at an academic center, 5-14% received CAR-T therapy at a community center. Tocilizumab and corticosteroids were the most commonly used treatments for CRS, including 37-48% use of tocilizumab for Grade 1 CRS (Table 2). Discussion: This study uniquely summarizes RWD on CRS following the use of commercially available CAR-T therapies across multiple hematologic malignancies, based on information from clinical notes abstracted retrospectively from EHRs. Consistent with the timing of approval of commercially available CAR-T therapies, the sample size for MM was limited compared with other malignancies. Safety events are typically under-reported in RWD sources, specifically for CRS when relying on information documented in patients' EHRs, compared with other published literature. In accordance with other RWD on CRS, grading criteria for CRS as well as vasopressor and oxygen use were not consistently reported in patients' EHRs. CAR-T treatments were predominantly administered in academic centers. Limited use in community practices was also observed; however, further information to accurately characterize the size and capabilities of community centers was not available in this database. Data also showed considerable use of tocilizumab to treat low-grade CRS, suggesting the need for additional evidence on its role to treat CRS beyond its current regulatory approval. Increased evidence generation, specifically from usual clinical practice, can contribute to increased awareness and knowledge about CRS diagnosis and management, and in turn realize the maximum potential of T-cell therapeutics.

Preclinical Evaluation of Bisantrene As Single Agent and in Combination with Decitabine for Acute Myeloid Leukemia

Anthracyclines, particularly doxorubicin and idarubicin, together with cytarabine, have comprised standard of care induction chemotherapy in acute myeloid leukemia (AML) for almost 4 decades. Although 60% of patients achieve remission, the majority relapse within 1-2 years. As such, outcomes in AML remain poor, with overall 5-year survival around 27%. In elderly AML patients the situation is worse, with 80% dying within one year of diagnosis. Toxicity of induction therapy is a major barrier to treatment success, precluding many unfit and elderly patients. Hypomethylating agents (HMA; azacytidine, decitabine) provide a less toxic alternative and have improved treatment options for the unfit. However, only 50% of patients respond to HMA therapy and most eventually acquire resistance, resulting in relapse. Approaches that reduce the toxicity of induction therapy and improve the efficacy of HMA treatment are emerging, e.g. combinations with Venetoclax. Nevertheless, novel combination strategies that improve outcomes in certain mutation subtypes need to be explored. Bisantrene, an anthracene derivative developed over 4 decades ago as a less cardiotoxic chemotherapy alternative to anthracyclines, shows broad activity across multiple solid and haematological malignancies. Several clinical studies in the 1980s showed bisantrene is an effective AML salvage therapy, producing response rates up to 50% without accompanying cardiotoxicity (Rothman J., 2017 Int J Cancer Res Ther;2(2):1-10) In a recent investigator-led Phase II trial of heavily pre-treated relapsed/refractory AML patients, 1/10 achieved a complete remission and 3/10 patients achieved partial remission. Interestingly, all responders were characterised by extramedullary disease (Cannani et al., 2020 Eur J Haematol 2021;106:260-266). We postulate that bisantrene may represent a suitable candidate for combination with HMA in patients unfit for standard induction chemotherapy. To explore this idea, we evaluated the in vitro and in vivo effects of bisantrene both alone and in combination with decitabine. The in vitro activity of bisantrene was initially assessed in a range of human and mouse AML cell lines covering the major molecular and clinical subtypes. All cells were sensitive to bisantrene, showing IC 50 values in the range 16-563 nM. FLT3-ITD + cells in particular were sensitive, while NRAS, KRAS and KIT mutant lines were also responsive. When tested against primary patient AML samples, 15/49 (30.6%) responded strongly to bisantrene treatment ex vivo over the dose range 0.1-1 µM. Bisantrene was shown to induce G1 accumulation and dose-dependent apoptosis in the FLT3-ITD + cell line, MOLM13. When tested in combination with decitabine, pre-treatment with decitabine for 24 h followed by decitabine plus bisantrene for 3 days produced synergistic cytotoxicity in MOLM13, MV4-11 and OCI-AML3 cells. Bisantrene and decitabine together resulted in S phase accumulation in MOLM13 cells and synergistic induction of apoptosis. The in vivo efficacy of bisantrene alone and in combination with decitabine were examined using the MOLM13- luc cell line and a patient derived xenograft (PDX; AML16) (FLT3-ITD +, NPM1, IDH2 and WT1 mutant) in NSG mice. Bisantrene (10 mg/kg i.v. twice/week) significantly reduced leukemic burden and increased median survival compared to vehicle control in MOLM-13- luc engrafted mice, and significantly reduced leukemic burden and increased median survival in a dose and schedule-dependent manner (2.5mg/kg and 5mg/kg, twice or three times weekly) in the PDX model. The combination of bisantrene (5 or 10 mg/kg twice weekly) and decitabine (0.2 mg/kg i.p. 5 days/week) significantly improved survival in MOLM13- luc (Figure 1) and PDX AML16 (Figure 2) engrafted mice, respectively, relative to vehicle control and each single agent. The combination also reduced leukemic infiltration to extramedullary sites (spleen, liver, uterus, brain). These data support that addition of bisantrene to HMA backbone therapy may provide an important new treatment strategy in AML. A prospective Phase Ib/II trial is being planned to evaluate this new therapeutic approach.

Scalp Cooling to Prevent Hair Loss in Multiple Myeloma Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation

The best outcomes for multiple myeloma progression-free and overall survival include the use of high-dose melphalan and autologous peripheral blood stem cell transplantation. Melphalan is given at a dose of 140 - 200 mg/m2 as a single dose two days before or in divided daily doses immediately prior to the reinfusion of stem cells. Melphalan causes nearly complete hair loss in all patients at these doses, (CTCAE v5 Grade 2). Hair typically falls out after 10-15 days and doesn't begin to grow back for 10-12 weeks. This outcome is widely expected and leads some patients to avoid doing an otherwise life sustaining procedure. In those that do proceed with the transplant, the alopecia can be emotionally harmful. Cryotherapy is commonly used to reduce melphalan side effects in the GI tract. Melphalan typically will cause diarrhea, nausea, and mouth sores yet a randomized trial done in 2006 showed that swallowing ice chips for 6 hours starting 30 minutes before the melphalan is given can reduce these unpleasant and potentially dangerous side effects by 60% (Lilleby et. al. 2006). We at Cedars-Sinai routinely have patients do oral cryotherapy for 3.5 hours starting 30 minutes prior to each dose of melphalan. This has reduced patient side effects substantially in our experience and is considered our standard of care. Chemotherapy drugs, such as melphalan, typically injure bone marrow, intestinal lining and other cells with high metabolism and rapid cell division. Hair follicles also have these properties and is likely why many chemotherapeutics cause hair loss when used. Scalp cooling has been used to prevent hair loss in many patients undergoing chemotherapy for solid tumors. For some women with breast cancer, this hair loss was reported to be more traumatizing than losing a breast to mastectomy (Zhang et. al. 2022). The use of cold caps during chemotherapy exposure time has helped reduce hair loss, presumably by causing vasoconstriction and reducing distribution of the drug to the hair follicle. This intervention has been effective even when drugs which have longer durations of circulation have been given. While there is a theoretical risk that scalp cooling may impair the killing of malignant cells in the scalp by the chemotherapy, there is no evidence of a heightened risk in studies. The penetration of the cold should not reach the skull bone where myeloma cells may reside and is generally to a depth of only a few millimeters. The toxicity of scalp cooling is minimal. In a study of 27 participants using scalp cooling for solid tumors, 96% reported that the procedure was worth the time, effort, cost, and discomfort and would recommend usage to others undergoing the same chemotherapy treatment (Sitarz et. al. 2022). While scalp cooling has been used to prevent hair loss in patients undergoing chemotherapy for solid tumors, no reports were found for its usage for multiple myeloma or other hematologic malignancies. Since melphalan has a much shorter half-life, (70 minutes), than most other chemotherapy drugs used for solid tumors, it is anticipated that scalp cooling will be more efficacious when used with this drug. In fact, after 5 hours the concentration of melphalan should only be 5% of that present immediately after administration. A 57-year-old patient with multiple myeloma undergoing high-dose chemotherapy with melphalan 200 mg/m2 opted to use the commercially available Penguin Cold Cap to prevent losing her hair. The device was started 60 minutes before and continued for 5 hours after the melphalan infusion was started at Day -2 and Day -1 prior to her autologous stem cell transplant. The procedure was well tolerated, and the patient had no signs of any hair loss after the stem cell transplant. Based upon this experience, a study was initiated to further assess the efficacy of scalp cooling with the Penguin Cold Cap device in multiple myeloma patients receiving autologous stem cell transplants. An update with results of this study will be presented at the meeting. A positive outcome may improve the percentage of people willing to undergo this life-sustaining procedure and improve the quality of life of those who do it.

A Novel Selective BCL2 Inhibitor with Limited Immune Suppression and Improved Safety Compared to Venetoclax

BCL2 is a key pro-survival protein that is overexpressed in many cancers. The first generation BCL2 inhibitor venetoclax has proved highly effective in multiple hematological malignancies including CLL and AML. However, the pharmacokinetic half-life of venetoclax is 26 hours which prevents optimization of the therapeutic window. Additionally, venetoclax metabolism is influenced by Cyp3A/4 inhibitors making their use in diseases where anti-fungal prophylaxis is required challenging. Venetoclax treatment can also result in significant immunosuppression including dose-limiting neutropenia and thrombocytopenia, and the loss of multiple lymphocyte populations, due in part to its effect on BCL-xL. Herein we present the pre-clinical evaluation of a novel highly selective BCL2 inhibitor, ZE50-0134, with equivalent anti-tumor efficacy, improved safety profile, and limited impact on non-malignant immune populations. ZE50-0134 binds the P2 pocket of BCL2, thereby increasing selectivity toward BCL-2, ZE50-0134 showed a 4600-fold greater selectivity for BCL2 over BCL-xL compared to venetoclax with only an 84-fold greater selectivity. In vivo murine and canine pharmacokinetics showed that ZE50-0134 has a substantially shorter half-life than venetoclax suggesting feasibility for periodic pulse dosing to limit the on-target adverse effects of BCL2 inhibition. The ADME properties of ZE50-0134 were exceptional. An in vivo murine study examining the pharmacology of ZE50-0134 or venetoclax given with ketoconazole, a strong CYP3A inhibitor, was performed demonstrating a 0.84-fold decrease in AUC with ZE50-0134 vs. a 1.52-fold increase in AUC with venetoclax suggesting less Cyp3A influence on ZE50-0134. Toxicology in rats and dogs suggest a 19-fold margin between therapeutically effective dose and toxicity with ZE50-0134. Given this data, we sought to validate that ZE50-0134 has less impact on normal immune populations. Wild-type C57BL6/J mice were treated daily with 100 mg/kg ZE50-0134, 100 mg/kg venetoclax or vehicle. A comprehensive 36-color spectral flow cytometry immune profiling panel was used to evaluate the effect of BCL2 inhibitors on multiple immune populations including B, T and NK cells as well as monocyte/macrophage and dendritic cell subsets in the peripheral blood. Venetoclax treated mice demonstrated a significant loss of multiple lymphocyte populations, including B, T, and NK cells, in the peripheral blood. Particularly, from Day 14 venetoclax treatment significantly reduced the percentage and absolute count of CD8 T cells (Figure 1). Some reduction in CD8 T cells was also observed with ZE50-0134 treatment, however it was significantly less than with venetoclax. No changes in the frequency of any normal myeloid population were observed. We next sought to examine the effectiveness of ZE50-0134 in B-cell and myeloid malignancies. Primary CLL cells were treated for 4 and 24 hours, corresponding to the expected half-life of ZE50-0134 and venetoclax, followed by washout. Cytotoxicity at 72 hours for both ZE50-0134 and venetoclax were equivalent for both short and prolonged treatment. We then assessed ZE50-0134 and venetoclax in vivo at 100 mg/kg in the RSV4;11 subcutaneous lymphoid model where we observed similar tumor growth regression. In AML, venetoclax is typically not effective as monotherapy and if often used in combination with azacytidine. To assess the relative efficacy of venetoclax and ZE50-0134 in combination with Azacitidine (5-Aza), we used the MOLM-13 cell line disseminated xenograft model. NCG mice were engrafted with MOLM-13 cells via the tail vein. From day 3, mice were treated with daily oral gavage of venetoclax or ZE50-0134 (100 mg/kg) alone or in combination with weekly intravenous 5-Aza (2.5 mg/kg). ZE50-0134 and venetoclax performed equally as single agents (median survival 23.5 days vs 22.5 days) and in combination with 5-Aza (median survival 35 days vs 35 days) (Figure 2). Together, this data suggests that ZE50-0134 is a highly effective BCL2 inhibitor with substantially less impact on the normal immune cells responsible for both anti-tumor and anti-infectious immunity. The pharmacology of this agent makes it an ideal therapeutic to optimize tumor BCL2 dependence and avoid untoward toxicity that occurs through continuous BCL2 targeting. This data supports the further clinical development of ZE50-0134 in both B cell malignancies and AML.

Disparities in dosing, drug reduction, and drug discontinuation among US FDA approved tyrosine kinase inhibitors

Background: Tyrosine kinase inhibitors (TKIs) have altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. However, patients are started on lower doses in practice. We assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs and observed the disparity among study populations to understand if there was adequate representation of diversity in race. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, race, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: Among all TKIs, median dose was 200 mg and average dose was 307.7 mg; 36 (24%) were approved bid vs 107 (72%) qd. Among approved indications, median rates of dose reduction rate (DRR), drug interruption rate (DIR), drug discontinuations rate (DDR) were 31%, 52%, and 10% respectively. Reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Black and Hispanic races are consistently underrepresented among the TKI studies. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate but these studies were done mostly in White individuals. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients while broadening the study population so that the studies will be generalizable to patients in clinical practice. Future studies are warranted to increase representation in the studies to address the disparities.

SGLT2i Dapagliflozin decreases NLRP3, IL-1 and PCSK9 expression in preclinical models of short-term doxorubicin cardiotoxicity

Abstract Background Anthracyclines are an effective and widely used chemotherapy agent in the treatment of multiple solid organ tumors and hematologic malignancies. The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure. In recent five years, it was demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), a lipid metabolism-related protein, is a key orchestrator of immune infiltration in myocardial and cancer tissues and could regulate cardiac fibrosis and inflammation. PCSK9 is a protein with key roles in hepatic low density lipoprotein (LDL) homeostasis. PCSK9 systemic levels are associated to HOMA score and high insulin levels. Dapagliflozin exerts systemic ant-inflammatory properties and cardioprotective effects in diabetic and non-diabetic patients. Purpose We hypothesized that Dapagliflozin, administered during doxorubicin, could reduce PCSK9 systemic levels in preclinical models. Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). After treatments, plasma levels of PCSK9, IL-1β and CRP were analyzed through selective anti-mouse ELISA methods. Myocardial and liver expression of NLRP3-inflammasome and IL-1β were analyzed through ELISA method in tissue lysates after treatments. Results DAPA associated to DOXO reduces significantly systemic levels of PCSK9 ( -37,5% vs DOXO group, p&amp;lt;0,001). IL-1β and CRP levels were also reduced ( -47,3 and – 28,5 %, respectively; p&amp;lt;0.05 for both). Myocardial and liver IL-1β and NLRP3 inflammasome expression were also reduced in DAPA/DOXO group vs DOXO and control, indicated beneficial metabolic and anti-inflammatory effects of SGLT2i. Conclusion DAPA has been shown to reduce systemic levels of PCSK9 in preclinical models of short-term DOXO cardiotoxicity. To the best of our knowledge, this is the first evidence of SGLT-2/PCSK9 crass-talk in cardioncology therefore the overall picture of the study open a new window on the beneficial properties of DAPA against anthracyclines side effects.

Abstract 15043: Dapagliflozin Reduces Systemic NLRP-3, IL-1 and PCSK9 Levels in Preclinical Models of Short-Term Doxorubicin Cardiotoxicity: New Evidences of SGLT2i Use in Cardioncology

Background: Anthracyclines are an effective and widely used chemotherapy agent in the treatment of multiple solid organ tumors and hematologic malignancies. The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure. In recent five years, it was demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), a lipid metabolism-related protein, is a key orchestrator of immune infiltration in myocardial and cancer tissues and could regulate cardiac fibrosis and inflammation. PCSK9 is a protein with key roles in hepatic low density lipoprotein (LDL) homeostasis. PCSK9 systemic levels are associated to HOMA score and high insulin levels. Dapagliflozin exerts systemic ant-inflammatory properties and cardioprotective effects in diabetic and non-diabetic patients. Purpose: We hypothesized that Dapagliflozin, administered during doxorubicin, could reduce PCSK9 systemic levels in preclinical models. Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). After treatments, plasma levels of PCSK9, IL-1β and CRP were analyzed through selective anti-mouse ELISA methods. Myocardial and liver expression of NLRP3-inflammasome and IL-1β were analyzed through ELISA method in tissue lysates after treatments. Results: DAPA associated to DOXO reduces significantly systemic levels of PCSK9 ( -37,5% vs DOXO group, p&lt;0,001). IL-1β and CRP levels were also reduced ( -47,3 and - 28,5 %, respectively; p&lt;0.05 for both). Myocardial and liver IL-1β and NLRP3 inflammasome expression were also reduced in DAPA/DOXO group vs DOXO and control, indicated beneficial metabolic and anti-inflammatory effects of SGLT2i. Conclusion: DAPA has been shown to reduce systemic levels of PCSK9 in preclinical models of short-term DOXO cardiotoxicity. To the best of our knowledge, this is the first evidence of SGLT-2/PCSK9 crass-talk in cardioncology therefore the overall picture of the study open a new window on the beneficial properties of DAPA against anthracyclines side effects.

Hematopoietic stem cell transplantation and the noncytomegalovirus herpesviruses.

Although hematopoietic stem cell transplantation (HSCT) and other cellular therapies have significantly improved outcomes in the management of multiple hematological and nonhematological malignancies, the resulting impairment in humoral and cellular response increases the risk for opportunistic infection as an undesirable side effect. With their ability to establish latent infection and reactivate when the host immune system is at its weakest point, the Herpesviridae family constitutes a significant proportion of these opportunistic pathogens. Despite recent advancements in preventing and managing herpesvirus infections, they continue to be a common cause of significant morbidity and mortality in transplanted patients. Herein, we aim to provide and update on herpesvirus other than cytomegalovirus (CMV) affecting recipients of HSCT and other cellular therapies.

Reinforced antimyeloma therapy via dual-lymphoid activation mediated by a panel of antibodies armed with bridging-BiTE

AbstractImmunotherapy using bispecific antibodies including bispecific T-cell engager (BiTE) has the potential to enhance the efficacy of treatment for relapsed/refractory multiple myeloma. However, myeloma may still recur after treatment because of downregulation of a target antigen and/or myeloma cell heterogeneity. To strengthen immunotherapy for myeloma while overcoming its characteristics, we have newly developed a BiTE-based modality, referred to as bridging-BiTE (B-BiTE). B-BiTE was able to bind to both a human immunoglobulin G–Fc domain and the CD3 molecule. Clinically available monoclonal antibodies (mAbs) were bound with B-BiTE before administration, and the mAb/B-BiTE complex induced antitumor T-cell responses successfully while preserving and supporting natural killer cell reactivity, resulting in enhanced antimyeloma effects via dual-lymphoid activation. In contrast, any unwanted off-target immune-cell reactivity mediated by mAb/B-BiTE complexes or B-BiTE itself appeared not to be observed in vitro and in vivo. Importantly, sequential immunotherapy using 2 different mAb/B-BiTE complexes appeared to circumvent myeloma cell antigen escape, and further augmented immune responses to myeloma relative to those induced by mAb/B-BiTE monotherapy or sequential therapy with 2 mAbs in the absence of B-BiTE. Therefore, this modality facilitates easy and prompt generation of a broad panel of bispecific antibodies that can induce deep and durable antitumor responses in the presence of clinically available mAbs, supporting further advancement of reinforced immunotherapy for multiple myeloma and other refractory hematologic malignancies.

Infectious complications among patients receiving ibrutinib for the treatment of hematological malignancies.

Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat multiple hematologic malignancies and graft-versus-host disease. Though less myelosuppressive than cytotoxic chemotherapy, increased infections, including invasive fungal infections (IFIs), have been reported with ibrutinib use. This study aimed to determine the characteristics and risk factors for infection associated with ibrutinib at our institution. Patients who received ibrutinib between June 2014 and August 2019 were included. Primary endpoints were the incidence of any infection and the incidence of serious infection (defined as hospitalization, parenteral antimicrobial therapy, or pneumonia regardless of hospitalization). Infection risk factors were assessed using logistic regression. One hundred thirty-two patients were identified (78% male; median age, 71 years). The most common indications for ibrutinib were chronic lymphocytic leukemia (67%) and mantle cell lymphoma (12%). Infection and serious infection occurred in 94 (71%) and 47 (36%) patients, respectively; when pneumonia was excluded as a criterion for serious infection, the serious infection rate was 27%. The median time from ibrutinib initiation to first infection was 125 days. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) (odds ratio [OR], 4.60; 95% CI, 1.22-17.4) and corticosteroid use (OR, 5.55; 95% CI, 1.52-20.3) were significant risk factors for serious infection. IFIs were diagnosed in 7 patients (5%): 5 had Pneumocystis jirovecii pneumonia and 2 were infected with invasive molds. Serious infection and IFI rates are high but similar to those previously described. Risk factors for serious infection included allo-HSCT and corticosteroid use. Targeted antimicrobial prophylaxis should be evaluated in prospective studies in patients on ibrutinib to reduce serious infections and IFI.

Improving the cytotoxicity of immunotoxins by reducing the affinity of the antibody in acidic pH

BackgroundImmunotoxins are antibody-toxin conjugates that bind to surface antigens and exert effective cytotoxic activity after internalization into tumor cells. Immunotoxins exhibit effective cytotoxicity and have been approved by the FDA to treat multiple hematological malignancies, such as hairy cell leukemia and cutaneous T-cell lymphoma. However, most of the internalized immunotoxin is degraded in lysosomes, and only approximately 5% of free toxin escapes into the cytosol to exert cytotoxicity. Many studies have improved immunotoxins by engineering the toxin fragment to reduce immunogenicity or increase stability, but how the antibody fragment contributes to the activity of immunotoxins has not been well demonstrated.MethodsIn the current study, we used 32A9 and 42A1, two anti-GPC3 antibodies with similar antigen-binding capabilities and internalization rates, to construct scFv-mPE24 immunotoxins and evaluated their in vitro and in vivo antitumor activities. Next, the antigen-binding capacity, trafficking, intracellular protein stability and release of free toxin of 32A9 scFv-mPE24 and 42A1 scFv-mPE24 were compared to elucidate their different antitumor activities. Furthermore, we used a lysosome inhibitor to evaluate the degradation behavior of 32A9 scFv-mPE24 and 42A1 scFv-mPE24. Finally, the antigen-binding patterns of 32A9 and 42A1 were compared under neutral and acidic pH conditions.ResultsAlthough 32A9 and 42A1 had similar antigen binding capacities and internalization rates, 32A9 scFv-mPE24 had superior antitumor activity compared to 42A1 scFv-mPE24. We found that 32A9 scFv-mPE24 exhibited faster degradation and drove efficient free toxin release compared to 42A1 scFv-mPE24. These phenomena were determined by the different degradation behaviors of 32A9 scFv-mPE24 and 42A1 scFv-mPE24 in lysosomes. Moreover, 32A9 was sensitive to the low-pH environment, which made the 32A9 conjugate easily lose antigen binding and undergo degradation in lysosomes, and the free toxin was then efficiently produced to exert cytotoxicity, whereas 42A1 was resistant to the acidic environment, which kept the 42A1 conjugate relatively stable in lysosomes and delayed the release of free toxin.ConclusionsThese results showed that a low pH-sensitive antibody-based immunotoxin degraded faster in lysosomes, caused effective free toxin release, and led to improved cytotoxicity compared to an immunotoxin based on a normal antibody. Our findings suggested that a low pH-sensitive antibody might have an advantage in the design of immunotoxins and other lysosomal degradation-dependent antibody conjugate drugs.

Phase 1/2 study of PRO1160, a CD70-directed antibody-drug conjugate, in patients with advanced solid tumors and hematologic malignancies

Abstract Background: PRO1160 is a novel antibody-drug conjugate (ADC) directed to CD70, an antigen mediating immuno-suppression that is overexpressed in multiple solid tumors and hematologic malignancies, with limited distribution in normal tissues. PRO1160 comprises (1) a human monoclonal antibody specific for CD70, (2) a protease-cleavable proprietary hydrophilic linker, and (3) exatecan, a topoisomerase 1 inhibitor. Comprehensive prior work demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetics (PK) across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance pumps, thus likely lending strong bystander effects and durable treatment responses. PRO1160 is highly potent in cell-derived xenograft models of renal cell carcinoma (RCC), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). PRO1160 also demonstrates marked antitumor activity in patient-derived xenograft models of diverse tumor sites, histologies, molecular subtypes, target expression levels, and Epstein Barr Virus status. PRO1160 is stable in circulation and displays PK characteristics indistinguishable from the parent antibody in rats. In a GLP toxicity study in cynomolgus monkeys, the primary PRO1160-related toxicity resided in the thymus and bone marrow, was consistent with exatecan toxicities, and was reversible. PRO1160-001 is an ongoing, open-label Phase 1/2 study to evaluate the safety, tolerability, PK, and antitumor activity of PRO1160 in patients with metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or the Lugano Classification for NHL. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1160 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1160 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). This study consists of 2 parts, Part A: dose-escalation and dose-level expansion, and Part B: 3 tumor-specific expansion cohorts (metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL) treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (Clinicaltrials.gov: NCT05721222).