Treatment Of Hematological Cancers Research Articles

From TCR fundamental research to innovative chimeric antigen receptor design.

Engineered T cells that express chimeric antigen receptors (CARs) have transformed the treatment of haematological cancers. CARs combine the tumour-antigen-binding function of antibodies with the signalling functions of the T-=cell receptor (TCR) ζ chain and co-stimulatory receptors. The resulting constructs aim to mimic the TCR-based and co-receptor-based activation of T cells. Although these have been successful for some types of cancer, new CAR formats are needed, to limit side effects and broaden their use to solid cancers. Insights into the mechanisms of TCR signalling, including the identification of signalling motifs that are not present in the TCR ζ chain and mechanistic insights in TCR activation, have enabled the development of CAR formats that outcompete the current CARs in preclinical mouse models and clinical trials. In this Perspective, we explore the mechanistic rationale behind new CAR designs.

From Deworming to Cancer Therapy: Benzimidazoles in Hematological Malignancies.

Drug repurposing is a strategy to discover new therapeutic uses for existing drugs, which have well-established toxicity profiles and are often more affordable. This approach has gained significant attention in recent years due to the high costs and low success rates associated with traditional drug development. Drug repositioning offers a more time- and cost-effective path for identifying new treatments. Several FDA-approved non-chemotherapy drugs have been investigated for their anticancer potential. Among these, anthelmintic benzimidazoles (such as albendazole, mebendazole, and flubendazole) have garnered interest due to their effects on microtubules and oncogenic signaling pathways. Blood cancers, which frequently develop resistance and have high mortality rates, present a critical need for effective therapies. This review highlights the recent advances in repurposing benzimidazoles for blood malignancies. These compounds induce cell cycle arrest, differentiation, tubulin depolymerization, loss of heterozygosity, proteasomal degradation, and inhibit oncogenic signaling to exert their anticancer effects. We also discuss current limitations and strategies to overcome them, emphasizing the potential of combining benzimidazoles with standard therapies for improved treatment of hematological cancers.

In Vivo Monitoring and Magnetically‐Enhanced Delivery of CAR T‐Cells to Solid Tumor

AbstractChimeric antigen receptor (CAR) T‐cell therapy demonstrates efficacy for the treatment of hematologic cancers, but remains challenging in solid tumors because of the hostile tumor microenvironment and heterogeneity that restrict the infiltration and activity of CAR T‐cells. The lack of clinical imaging methods to monitor CAR T‐cell therapy in patients limits the potential to enhance the therapeutic approach and predict patient response. Here, a straightforward, non‐invasive method for Magnetic Resonance Imaging (MRI) tracking and magnetic targeting of CAR T‐cells to enhance T‐cell trafficking to solid tumors, in a setting that can be deployed in clinics, is reported. Iron oxide nanoparticles are loaded into T‐cells, allowing MRI detection and magnetic cell guidance, while preserving T‐cell viability, functions, and CAR specificity to target epidermal growth factor receptor (EGFR)‐expressing tumors. Longitudinal MRI monitoring of T‐cells over 14 days reveals differences in tumor infiltration rates and antitumor efficacy between EGFR‐targeted CAR T‐cells and non‐transduced T‐cell. Moreover, an external magnet placed over the tumor enhances the infiltration of CAR T‐cells and increases their antitumor effect. MRI monitoring and magnetic guidance represent a dual‐pronged clinically feasible therapeutic strategy to control and promote CAR T‐cells delivery into solid tumors, thereby improving the precision, efficacy, and safety of the treatment.

Enhancing Fc-mediated effector functions of monoclonal antibodies: The example of HexaBodies.

Since the approval of the CD20-targeting monoclonal antibody (mAb) rituximab for the treatment of lymphoma in 1997, mAb therapy has significantly transformed cancer treatment. With over 90 FDA-approved mAbs for the treatment of various hematological and solid cancers, modern cancer treatment relies heavily on these therapies. The overwhelming success of mAbs as cancer therapeutics is attributed to their broad applicability, high safety profile, and precise targeting of cancer-associated surface antigens. Furthermore, mAbs can induce various anti-tumor cytotoxic effector mechanisms including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), all of which are mediated via their fragment crystallizable (Fc) domain. Over the past decades, these effector mechanisms have been substantially improved through Fc domain engineering. In this review, we will outline the different approaches to enhance Fc effector functions via Fc engineering of mAbs, with a specific emphasis on the so-called "HexaBody" technology, which is designed to enhance the hexamerization of mAbs on the target cell surface, thereby inducing greater complement activation, CDC, and receptor clustering. The review will summarize the development, preclinical, and clinical testing of several HexaBodies designed for the treatment of B-cell malignancies, as well as the potential use of the HexaBody technology beyond Fc-mediated effector functions.

Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential.

In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss the synergistic potential of combining inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include combining PI3K inhibitors with proteasome inhibitors, NF-κB inhibitors with immunotherapy checkpoint inhibitors, and neddylation inhibitors with therapies targeting the tumor microenvironment. Additionally, we discuss the potential use of small molecules and peptide inhibitors in hematologic cancer treatment. These multidimensional therapeutic combinations present promising strategies for enhancing treatment efficacy and overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness and safety profiles in hematologic cancer patients.

Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation

BackgroundTargeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.MethodsPhenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression.ResultsWe identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment.ConclusionsOur findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Cardiovascular toxicities of immune therapies for cancer-a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Nogapendekin alfa Inbakicept: First Approval.

Nogapendekin alfa inbakicept (ANKTIVA®; nogapendekin alfa inbakicept-pmln) is a recombinant interleukin-15 (IL-15) superagonist protein complex being developed by Altor BioScience, LLC, an indirect wholly owned subsidiary of ImmunityBio, Inc., for the treatment of solid and haematological cancers and HIV infection. In April 2024, nogapendekin alfa inbakicept was approved for use with Bacillus Calmette-Guérin (BCG) for the treatment of adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours in the USA. This article summarizes the milestones in the development of nogapendekin alfa inbakicept leading to this first approval for the treatment of cancer.

Universal CAR 2.0 to overcome current limitations in CAR therapy.

Chimeric antigen receptor (CAR) T cell therapy has effectively complemented the treatment of advanced relapsed and refractory hematological cancers. The remarkable achievements of CD19- and BCMA-CAR T therapies have raised high expectations within the fields of hematology and oncology. These groundbreaking successes are propelling a collective aspiration to extend the reach of CAR therapies beyond B-lineage malignancies. Advanced CAR technologies have created a momentum to surmount the limitations of conventional CAR concepts. Most importantly, innovations that enable combinatorial targeting to address target antigen heterogeneity, using versatile adapter CAR concepts in conjunction with recent transformative next-generation CAR design, offer the promise to overcome both the bottleneck associated with CAR manufacturing and patient-individualized treatment regimens. In this comprehensive review, we delineate the fundamental prerequisites, navigate through pivotal challenges, and elucidate strategic approaches, all aimed at paving the way for the future establishment of multitargeted immunotherapies using universal CAR technologies.

Hematopoietic stem cell transplantation and cellular therapy in persons living with HIV.

Summarize the latest research of both stem cell transplantation and cellular therapy and present the implications with respect to persons with HIV (PWH), hematologic malignancies, and HIV-1 cure. Allogeneic (alloSCT) and autologous (autoSCT) stem cell transplantation have been shown to be well tolerated and effective regardless of HIV-1 status. AlloSCT leads to a decrease in the HIV-1 latently infected reservoir orders of magnitude below that achieved with antiretroviral therapy (ART) alone. Utilization of CCR5Δ2/Δ32 donors in an alloSCT has resulted in HIV-1 cures. In the last 12 months, three cases of cure have been published, giving further insight into the conditions required for HIV-1 control. Other advances in the treatment of hematological cancers include chimeric antigen receptor T-cell (CART) therapy, which are active in PWH with lymphoma. Here we discuss the advances in SCT and cellular therapy in PWH and cancer. Additionally, we discuss how these technologies are being utilized to achieve HIV-1 cure.

Deep phenotyping of nodal T-cell lymphomas reveals immune alterations and therapeutic targets.

Whereas immunotherapies have revolutionized the treatment of different solid and hematological cancers, their efficacy in nodal peripheral T-cell lymphomas (PTCLs) is limited, due to a lack of understanding of the immune response they trigger. To fully characterize the immune tumor microenvironment (TME) of PTCLs, we performed spectral flow cytometry analyses on 11 angioimmunoblastic T-cell lymphomas (AITL), 7 PTCL, not otherwise specified (PTCL, NOS) lymph node samples, and 10 non-tumoral control samples. The PTCL TME contained a larger proportion of regulatory T cells and exhausted CD8+ T cells, with enriched expression of druggable immune checkpoints. Interestingly, CD39 expression was up-regulated at the surface of most immune cells, and a multi-immunofluorescence analyses on a retrospective cohort of 43 AITL patients demonstrated a significant association between high CD39 expression by T cells and poor patient prognosis. Together, our study unravels the complex TME of nodal PTCLs, identifies targetable immune checkpoints, and highlights CD39 as a novel prognostic factor.

Valrubicin-loaded immunoliposomes for specific vesicle-mediated cell death in the treatment of hematological cancers

We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily incorporated Val-lLs that were loaded with specific antibodies. Val-ILs injected intravenously rapidly reached the bone marrow and spleen, indicating their potential to effectively target cancer cells in these areas. Following the transplantation of human pediatric B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) in immunodeficient NSG mice, we generated patient-derived xenograft (PDX) models, which were treated with Val-ILs loaded with antibodies to target CD19, CD7 or CD33. Only a small amount of valrubicin incorporated into Val-ILs was needed to induce leukemia cell death in vivo, suggesting that this approach could be used to efficiently treat acute leukemia cells. We also demonstrated that Val-ILs could reduce the risk of contamination of CD34+ hematopoietic stem cells by acute leukemia cells during autologous peripheral blood stem cell transplantation, which is a significant advantage for clinical applications. Using EL4 lymphoma cells on immunocompetent C57BL/6 mice, we also highlighted the potential of Val-ILs to target immunosuppressive cell populations in the spleen, which could be valuable in impairing cancer cell expansion, particularly in lymphoma cases. The most efficient Val-ILs were found to be those loaded with CD11b or CD223 antibodies, which, respectively, target the myeloid-derived suppressor cells (MDSC) or the lymphocyte-activation gene 3 (LAG-3 or CD223) on T4 lymphocytes. This study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Val-ILs as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.

Antibody-drug conjugates in solid tumors; new strategy for cancer therapy.

Antibody-drug conjugates (ADCs) have emerged as a novel class of anticancer treatment. ADCs are composed of three parts: a monoclonal antibody, a linker and a payload. A monoclonal antibody binds to the specific antigen present at the cancer cells, allowing selective delivery of the cytotoxic agents to the tumor site. Several ADCs are approved by the US Food and Drug Administration for the treatment of hematologic cancers and solid tumors with clinically meaningful survival benefit. However, the development of ADCs faces a lot of challenges and there is a need to get better understanding of ADCs in order to improve patient outcomes. Here, we briefly discuss the structure and mechanism of ADCs, as well as the clinical data of current approved ADCs in solid tumors.

“Don't keep me waiting”: estimating the impact of reduced vein-to-vein time on lifetime US 3L+ LBCL patient outcomes

AbstractChimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment of hematological cancers. Its production requires a complex logistical process, and the time from leukapheresis to patient infusion (known as the vein-to-vein time [V2VT]) can be long during which a patients clinical condition may deteriorate. This study was designed to estimate the benefits of reduced V2VT for third-line or later (3L+) relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with CAR T. A mathematical model was developed to estimate the lifetime outcomes of a hypothetical cohort of patients who had either a long or short V2VT. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were estimated. Scenario analyses were performed to assess the robustness of results to key assumptions. The results of the model show that reducing V2VT from 54 days (tisa-cel median V2VT; JULIET) to 24 days (axi-cel median V2VT; ZUMA-1) led to a 3.2-year gain in life expectancy (4.2 vs 7.7 LYs), and 2.4 additional QALYs (3.2 vs 5.6) per patient. Furthermore, a shorter V2VT was shown to be cost-effective under conventional willingness-to-pay thresholds in the United States. Results are driven by a higher infusion rate and a better efficacy of CAR T for those infused. Scenario analyses using a smaller difference in V2VT (24 vs 36 days) produced consistent results. Our study is the first to quantify lifetime V2VT-related outcomes for 3L+ R/R LBCL patients treated with CAR T utilizing currently available evidence. Shorter V2VTs led to improved outcomes, demonstrating the importance of timely infusion achievable by faster manufacturing times and optimization of hospital delivery.

Abstract 6719: TriTCE Co-Stim: A next generation trispecific T cell engager platform with integrated CD28 costimulation, engineered to improve responses in the treatment of solid tumors

Abstract Bispecific T cell engagers (TCEs) have exhibited clinical successes in the treatment of hematological cancers, while treatment of solid tumors remains a challenge. Treatment of solid tumors with conventional CD3-engaging TCEs can result in limited T cell proliferation and recruitment to the tumor site, and treatment related T cell anergy, thus restricting the ability of bispecific TCEs to inhibit growth of these poorly infiltrated tumors and rapidly growing tumors. Next generation tumor-targeting, trispecific T cell engagers with integrated costimulation (TriTCE Co-Stim) have the potential to provide more durable responses and re-invigorate T cell responses by mediating integrated signaling through CD3 (signal 1) and co-stimulation through CD28 (signal 2). Superagonist anti-CD28 antibodies activate T cells but resulted in clinical toxicities with severe cytokine release syndrome (CRS). Therefore, achieving a balance between signal 1 and 2 is critical for optimal T cell activation and proliferation. Using our AzymetricTM and EFECTTM platforms, we generated heterodimeric TriTCE Co-Stim antibody formats with various geometries and affinities to optimize T cell response and widen the therapeutic window for the treatment of solid tumors. We have previously described screening and interrogation of different TriTCE Co-stim formats and paratope affinities, and the selection of a lead format with optimized CD3 and CD28 T cell activation. Here, we have further expanded our validation of the TriTCE Co-stim platform with our lead CLDN18.2 TriTCE co-stim format, to include a tolerability assessment in nonhuman primates.Our lead TriTCE Co-Stim format exhibited a favorable safety profile in vitro and mediated target-dependent induction of T cell activity, with enhanced proliferation, survival, and T cell-mediated cytotoxic potency compared to bispecific TCEs. In a predictive in vivo model of CRS, our lead TriTCE Co-Stim did not exhibit systemic toxicity or peripheral cytokine release. TriTCE Co-Stim mediated enhanced tumor growth regression in vivo with an increase of T cells within the tumor and no increase of T cells within the periphery. Repeat doses of the lead TriTCE Co-Stim molecule at 3 mg/kg were well-tolerated in nonhuman primates with no abnormal clinical signs. Minor decreases in body weight and food consumption were observed. Clinical pathology changes were consistent with a mild systemic inflammatory response. In summary, our lead TriTCE co-stim molecule has enhanced target-dependent antitumor activity vs. bispecific benchmarks and is tolerated a murine CRS model and repeat dose non-human primate study. These data suggest TriTCE Co-stim may provide tolerable and more durable antitumor responses and contribute to improved clinical outcomes. Citation Format: Lisa Newhook, Purva Bhojane, Kurt Stahl, Nichole E. Escalante, Peter Repenning, Diego Perez Escanda, Polly Shao, Maya C. Poffenberger, Alec Robinson, Kesha Patel, Alexandra Livernois, Chayne L. Piscitelli, Nicole Afacan, Paul A. Moore, Nina E. Weisser, Thomas Spreter von Kreudenstein. TriTCE Co-Stim: A next generation trispecific T cell engager platform with integrated CD28 costimulation, engineered to improve responses in the treatment of solid tumors [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 6719.

Abstract 6708: MAIT engagers: Bispecific antibody-mediated redirection of mucosal associated invariant T cells to treat solid tumors

Abstract Background. Using bispecific antibodies (BiXAb) to redirect T cells to engage and kill cancer cells is an efficacious modality in the treatment of haematological cancers but has had limited success in the treatment of solid tumors. Mucosal-Associated Invariant T cells (MAITs) are an abundant subset of non-conventional T-cells with potent cytotoxic capacity (up to 20% of circulating T-cells) that are naturally resident in many tissues and solid tumors. MAIT cells utilize a semi-invariant TCR and recognize bacterial metabolites presented in the context of the MR1 protein. Biomunex has generated bispecific antibodies that bind the MAIT semi-invariant TCR (iTCR) and the HER2 receptor tyrosine kinase expressed on tumor cells. At difference to classical T-cell engagers that activate all T-cell subsets, MAIT engagers only modulate the activity of the cytotoxic MAIT cells leading to efficient tumor control and greater safety profile. Methods. Using the Biomunex proprietary BiXAb platform, bispecific, tetravalent antibodies were generated that target the MAIT iTCR and the HER2. MAIT-cell activation, proliferation and degranulation were followed by gating on MAIT cells within a purified CD8 cell population. Tumor cell lines (varying in [HER2] expression) were co-cultured with MAIT cells and the BiXAbs in several cytotoxic assays (evaluated by Chromium release). Cytokine release was assessed by Legend Plex assays or ELISA. Cytotoxicity of tumor-resident MAITs, from fresh patient samples, was determined by impedence measurements and in patient-derived 3D organoids by The Hub organoids (imaging). For in vivo analysis, sub-cutaneous tumor growth was measured with callipers. Results. MAIT engagers induce the rapid activation, proliferation and degranulation of MAIT cells leading to efficient killing of engaged HER2+ cancer cells with a potency similar to that of a classical HER2-directed TCE (in clinical development). The MAIT engager did not activate the regulatory T cells or other CD4/CD8 subsets. In addition, using PBMCs, total cytokine release was 1000-fold less with the MAIT engager compared to a classical TCE, opening up a large therapeutic window, which should permit effective treatment of solid tumors. Ex vivo cytotoxicity of tumor-resident MAIT cells using dissociated ovarian cancer samples at “real E:T ratios”, MAIT engager-mediated cytotoxicity of patient-derived organoids (CRC) and in vivo evaluation of tumor control will be shown. Conclusions. MAIT cell redirection is a promising approach for the treatment of solid tumors that has the potency and efficacy of a classical TCE but with a significantly improved cytokine safety profile leading to a larger therapeutic window. Citation Format: Simon Edward Plyte, Marie Fraudeau, Dorothee Winterberg, Claire Germain, Camille Rousseau, Gaetano Sodaro, Lise Fenou, Maxime Audin, Alexandre Ivagnes, Han-Heinrich Oberg, Pierre Emmanuel Gerard, Isabelle Navarro-Teulon, Daniela Wesch, Matthias Peipp, Julie Prigent. MAIT engagers: Bispecific antibody-mediated redirection of mucosal associated invariant T cells to treat solid tumors [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 6708.

Abstract 6714: AI-guided tailor-made anti-TROP2 T-cell engagers for T-cell mediated cancer immunotherapy with enhanced therapeutic index

Abstract Bispecific T-cell engagers (TCEs) have shown significant therapeutic advances in the treatment of hematologic cancers. However, the clinical efficacy of TCEs in treating solid tumors remains to be demonstrated. Accumulating evidence suggests novel TCE modalities that simultaneously engage both CD3 (signal 1) and CD28 (signal 2) co-stimulatory signals may offer potential advantage to enhance clinical efficacy of TCEs with improved therapeutic index. To explore the full potential of TCEs as a powerful approach of immunotherapy for solid tumors, we developed an integrated AI-guided TCE platform to streamline the discovery, optimization and high-throughput function screening and characterization of TCE molecules. Here we report the construction and characterization of a novel panel of TROP2-targeting TCEs by leveraging our AI-guided optimization technology, plus a high-throughput in vitro screening platform. These tailor-made TCE molecules exhibit favorable developability and functional properties. Our data show that a novel TROP2 × CD3 x CD28 trispecific TCE that contains a CD3-targeting arm in concomitant with a CD28-targeting arm can induce potent T-cell co-stimulation and promising synergistic T cell-mediated tumor cell killing in vitro, compared to its counterparts with a single CD3-targeting arm. We further generate a trivalent TROP2 x CD3 bispecific TCE constructed as an asymmetric ‘2+1’ format with bivalent binding to TROP2 but a monovalent CD3-targeting arm. This molecule stimulates very low levels of cytokine release, but drives robust antigen-specific killing in in vitro assessment. Anti-tumor activity of the various TROP2 x CD3 TCEs is currently being investigated in multiple tumor xenograft mouse models. Citation Format: Chuan Chen, Liang Tian, Chenpeng Su, Dandan Liu, Xiaoqian Chen, Yifei Zhou, Suze Jiang, Guifang Wang, Jiyuan Tian, Yuan Yuan, Bing Yang, Jian Peng. AI-guided tailor-made anti-TROP2 T-cell engagers for T-cell mediated cancer immunotherapy with enhanced therapeutic index [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 6714.

Abstract IA005: Regional combating of immunosuppressive forces in the ovarian tumor microenvironment

Abstract IA005: Regional combating of immunosuppressive forces in the ovarian tumor microenvironment

Effect of Silybum Marianum on Reduction of Chemotherapy-Induced Peripheral Neurotoxicity with Cisplatin.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the major complications of chemotherapy regimens commonly used in the treatment of solid and hematologic cancers. Given the high incidence of CIPN in antitumor therapies in patients and limited studies on antioxidants, this study was aimed to investigate the effect of Silybum marianum (SM) on cisplatin-induced peripheral neuropathy. This double-blind randomized clinical trial study was performed on 60 cancer patients treated with cisplatin chemotherapy at Seyyed-o-Shohada Hospital of Isfahan during 2019-2020. The patients were divided into two parallel groups as intervention (treated by SM) and placebo, and DN4 (Douleur neuropathique 4 questions) and CIPNAT (chemotherapy-induced peripheral neuropathy assessment tool) were completed for patients in the before and after intervention groups and compared between the two groups. The mean of DN4 score in the before and after study in the intervention group was in 1.76 ± 1.24 and 2.07 ± 2.03, respectively (P = 0.38), and in the control group was 1.41 ± 1.28 ± 3.11 ± 2.86, respectively (P = 0.012). The mean CIPNAT score in the intervention groups was 5.93 ± 3.65 and 4.20 ± 3.23 (P = 0.01), and in the control group was 4.20 ± 4.22 and 4.16 ± 4.03 (P = 0.39). Based on our data, SM is an effective agent in reducing peripheral neuropathy. The use of SM was associated with decreased scores of peripheral neuropathy and was helpful in patients undergoing chemotherapy with cisplatin.

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.