RB-1355 is distinguished by its unique mechanism of action which centers on the use of a patient’s own macrophages, a type of immune cell often residing in the tumor milieu. These macrophages are extracted and then subjected to an ex vivo hyperactivation process using proprietary methodologies designed to induce a robust pro-inflammatory and immune-supportive phenotype. This reprogramming effectively converts macrophages from potentially tumor-promoting actors to powerful anti-tumor effectors. Upon reintroduction into the patient’s lesions via direct intratumoral injections, these engineered macrophages reshape the tumor microenvironment by igniting a cascade of immune responses that encompass activation of neoantigen-specific T cells and B cells, thereby orchestrating a comprehensive immune assault on lymphoma cells.

One of the most compelling advantages of RB-1355 therapy is the rapid manufacturing pipeline, which allows for treatment readiness in approximately one week. This expedited timeline stands in stark contrast to other cell therapies which often require extended preparation periods, thereby making RB-1355 a more accessible option that can be deployed in a timely manner. Additionally, the therapy circumvents the need for lymphodepleting chemotherapy, a common preconditioning regimen that can cause considerable toxicity. This attribute not only enhances safety but also broadens the eligibility of patients who can receive the therapy irrespective of tumor mutational status, positioning RB-1355 as a versatile therapeutic across a spectrum of B-cell and T-cell lymphomas.

The initial clinical findings have been presented at the prestigious 2026 Tandem Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR), showcasing promising efficacy signals. Among thirteen heavily pretreated patients enrolled in the trial, two individuals with diffuse large B-cell lymphoma (DLBCL) achieved complete remission, notably including those who had previously failed CAR T cell therapy—a population with extremely limited treatment options. These responses, including durability beyond 100 days for one patient, underscore the potential of RB-1355 to address aggressive, refractory disease in a clinical setting.

In addition to complete remissions, partial responses were also observed in patients suffering from peripheral T-cell lymphoma and mycosis fungoides, malignancies traditionally resistant to standard therapies. This breadth of activity exemplifies RB-1355’s capacity to generate meaningful clinical benefit across heterogeneous lymphoma subtypes. Equally important is the favorable safety profile reported from the trial; no dose-limiting toxicities were encountered, and only three instances of low-grade adverse effects were noted, indicating that RB-1355 is not only efficacious but also well tolerated in a fragile patient population with limited alternatives.

From an immunological standpoint, the macrophage-centric approach of RB-1355 leverages the plasticity of these myeloid cells to break the immune tolerance often established in the tumor microenvironment. By instigating an inflammatory cascade, it promotes antigen presentation and stimulates both innate and adaptive immune components. This dual activation is critical for achieving sustained anti-lymphoma activity, given the complex immune evasion strategies employed by malignant lymphocytes. Furthermore, this method does not depend on the presence of specific actionable mutations in the lymphoma cells, enabling a broad-spectrum therapeutic effect that could redefine treatment algorithms for refractory lymphomas.

The potential implications for patients are profound. Historically, relapsed and refractory non-Hodgkin lymphoma cases have represented a therapeutic dead-end with limited durable options. RB-1355’s promising early results suggest it could fill this unmet need by offering a new avenue for disease control, especially for those who have exhausted conventional chemotherapy, targeted agents, and even advanced therapies like CAR T cells. The rapid preparation and administration of RB-1355 could also minimize delays in treatment initiation, a critical factor in managing aggressive lymphomas.

Current ongoing investigations aim to optimize RB-1355 through dose escalation and repeated treatment cycles to enhance the durability of responses and potentially increase remission rates. Researchers are also exploring synergistic combinations with other immunomodulatory agents to further amplify anti-lymphoma immunity. As the body of evidence grows, RB-1355 may represent the next frontier in cell therapy by expanding the types of immune cells engineered and by circumventing the limitations associated with existing therapies that primarily target T cells.

Moreover, the development of RB-1355 reflects a growing appreciation in oncology of the tumor microenvironment’s role in cancer progression and response to therapy. Unlike approaches that solely target malignant cells, therapies like RB-1355 aim to re-educate the immune ecosystem surrounding the tumor, creating an inhospitable environment for cancer cell survival. Such strategies could herald a new class of treatments for hematologic malignancies and potentially solid tumors, enabling a more holistic immune-based eradication of cancer.

The involvement of BobcatBio in supporting this research illustrates the critical importance of collaboration between academic institutions and biotechnology enterprises in translating cutting-edge science into clinical realities. The rapid translation from bench to bedside exemplifies how innovations in cellular manufacturing and immune engineering can swiftly impact patient care in fields where therapeutic needs remain urgent.

In conclusion, RB-1355 represents an innovative and promising cell therapy that reshapes the landscape of non-Hodgkin lymphoma treatment by utilizing hyperactivated macrophages to generate a multi-dimensional immune response without the need for conventional preconditioning regimens. Early clinical data show encouraging safety and efficacy profiles in patients with relapsed or refractory disease, including those unresponsive to CAR T therapies. Continued clinical development will delineate its role within the expanding arsenal against aggressive lymphomas, potentially offering hope to a patient population with critical unmet needs.

Subject of Research: Novel cell therapy RB-1355 for relapsed and refractory non-Hodgkin lymphoma

Article Title: RB-1355: A Macrophage-Based Cell Therapy Revolutionizing Treatment of Refractory Non-Hodgkin Lymphomas

News Publication Date: 2026 (Date of presentation at ASTCT/CIBMTR 2026 Tandem Meetings)

Web References:

• MD Anderson Non-Hodgkin Lymphoma Overview: https://www.mdanderson.org/cancer-types/non-hodgkin-lymphoma.html
• CAR T Cell Therapy at MD Anderson: https://www.mdanderson.org/treatment-options/car-t-cell-therapy.html
• Paolo Strati, M.D. Profile: https://faculty.mdanderson.org/profiles/paolo_strati.html
• ASTCT/CIBMTR Tandem Meetings 2026 Program: https://www.tandemmeetings.com/
• Full Abstract: https://tandem.virtual-meeting.org/programme/presentation/677607

Keywords:
Cell therapies, macrophage immunotherapy, non-Hodgkin lymphoma, relapsed lymphoma, refractory lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, mycosis fungoides, tumor microenvironment, immunotherapy, RB-1355, novel cancer treatments

The phase I trial, heralded as the first-in-human dose escalation study for OMT-110 in mCRC, enrolled fourteen patients over the age of twenty who had exhausted standard treatments. The study design meticulously evaluated escalating doses of OMT-110, administered subcutaneously in cycles of 21 days on treatment followed by a seven-day break. This regimen was sustained until patients exhibited either tumor progression, unacceptable toxicity, or voluntary withdrawal, ensuring rigorous monitoring of the drug’s tolerability over an extended period.

Safety assessment was a cornerstone of the trial, utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 to rigorously grade toxicities. Among the participants, a total of fifty-four adverse events were recorded, overwhelmingly of low-grade severity (grade 1 or 2). Notably, two serious adverse events were documented; however, thorough evaluation attributed these incidents as unrelated or probably unrelated to OMT-110 administration. This outcome suggests an encouraging safety margin that may allow for higher dosing and prolonged administration in future studies.

Pharmacokinetic analyses provided key insights into OMT-110’s behavior within the human body. Measurements before and after dosing revealed no significant drug accumulation after repeated cycles, a finding that underscores the drug’s favorable metabolic profile. Absence of accumulation reduces risks of unexpected toxicities and supports feasibility of sustained treatment schedules—a critical factor when managing advanced cancers with continuous systemic therapy.

Efficacy evaluations incorporated advanced imaging modalities, including abdominopelvic and chest computed tomography scans complemented by ^18F-fluorodeoxyglucose positron emission tomography/CT. These comprehensive radiological assessments adhered to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, providing a standardized framework to gauge tumor response. While this phase I study primarily focused on safety and dosing, initial pharmacodynamic signals hinted at therapeutic activity, which will be elaborated upon in subsequent trial phases.

After exhaustive dose escalation, 100 mg daily emerged as the recommended dose for phase II trials. This dosing recommendation is grounded not only in the manageable adverse event profile but also in pharmacodynamic markers and preliminary efficacy signals observed throughout the study period. A 28-day treatment cycle incorporating three weeks of active dosing followed by a one-week drug holiday appears to optimize the balance between therapeutic pressure on tumor cells and patient tolerability.

OMT-110’s unique mechanism, thought to involve immunomodulatory effects, places it at the cutting edge of cancer pharmacotherapy. Unlike traditional chemotherapeutics which directly target tumor proliferation pathways, immunomodulators harness the patient’s immune system, potentially leading to durable and adaptive anti-cancer responses. This novel angle is especially pertinent for mCRC patients who have failed to respond to conventional regimens, highlighting the urgency for innovative therapeutic modalities.

The trial’s rigor was further emphasized by stringent eligibility criteria ensuring enrollment of refractory mCRC patients with advanced disease states. Such inclusion criteria target a population with substantial unmet medical needs — individuals who often face limited therapeutic alternatives and poor prognoses. By navigating the challenges in this patient subset, the study underscores the trial’s translational significance and potential public health impact.

An intriguing aspect of the study was the pharmacodynamic monitoring through integrated imaging techniques combined with metabolic activity assessments via FDG-PET/CT. This convergence of functional and anatomical imaging not only offers real-time insights into tumor biology but may also serve as predictive biomarkers for therapeutic responsiveness. The development of such integrative diagnostic tools aligns with the broader movement towards personalized oncology.

In conclusion, this phase I investigation of OMT-110 represents a vital stepping stone towards novel systemic therapies for metastatic colorectal cancer. The demonstrated safety and tolerability, coupled with encouraging early efficacy signals and absence of pharmacokinetic accumulation, position OMT-110 as a viable candidate for more extensive clinical evaluation. These findings beckon continued research efforts in phase II trials to verify efficacy outcomes and further elucidate mechanistic underpinnings.

Beyond its immediate scientific contributions, the study also exemplifies the strategic repurposing of existing compounds—a practice increasingly valued for its cost-effectiveness and acceleration of drug development timelines. By leveraging prior pharmacological knowledge, researchers maximize resource utilization while expediting the delivery of new treatment options to patients in dire need.

As mCRC remains a significant global health burden with high mortality rates and limited effective treatments in refractory stages, advances such as OMT-110 offer a beacon of hope. Future research will likely explore combination regimens incorporating this agent alongside other immunotherapies or targeted drugs, potentially unlocking synergistic benefits that could redefine clinical outcomes.

The ongoing evaluation of OMT-110’s immunomodulatory properties may also illuminate broader oncological applications beyond colorectal cancer, given the increasing recognition of the tumor microenvironment’s role across various malignancies. Such versatility may position OMT-110 as a multi-indication therapeutic, expanding its relevance in oncology.

Ultimately, the scientific community and affected patients alike will watch closely as subsequent clinical trial phases unfold, with anticipation mounting around the potential of OMT-110 to transform standards of care for metastatic colorectal cancer. The journey from phase I to eventual regulatory approval is arduous but vital, and studies like this are foundational pillars that bring new hope to oncology’s forefront.

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Subject of Research:
The phase I clinical evaluation of OMT-110’s safety, tolerability, pharmacokinetics, and optimal dosing in patients with refractory metastatic colorectal cancer.

Article Title:
Phase I study of the safety, tolerability, and potential therapeutic dose of OMT-110 for patients with refractory metastatic Colorectal Cancer

Article References:
Jeon, Y., Jung, M., Jeong, B. et al. Phase I study of the safety, tolerability, and potential therapeutic dose of OMT-110 for patients with refractory metastatic Colorectal Cancer. BMC Cancer 25, 937 (2025). https://doi.org/10.1186/s12885-025-14351-1

Image Credits:
Scienmag.com

DOI:
https://doi.org/10.1186/s12885-025-14351-1

Colorectal cancer in its late stages poses a formidable challenge to clinicians and scientists alike. Despite significant progress in understanding the molecular underpinnings of this disease, stage IV colorectal cancer remains a largely incurable condition with limited treatment options. Dr. Emil Lou, a gastrointestinal oncologist and the study’s principal investigator, emphasizes the urgency of novel interventions, stating that this trial initiates a bold paradigm shift by bringing a laboratory innovation directly into the clinical setting. The approach is designed to leverage the body’s own immune system to recognize and eradicate metastatic tumor cells through precise genetic manipulation.

Central to this trial is the innovative use of the CRISPR/Cas9 system, a revolutionary gene-editing tool that allows scientists to make targeted alterations within the genome. The researchers focused on editing a critical intracellular immune checkpoint gene known as CISH, which naturally acts to suppress T cell activity within tumors. By knocking out CISH selectively within TILs isolated from patients’ tumors, the team effectively reprogrammed these immune cells to overcome the cancer’s defense mechanisms. This intracellular checkpoint had previously eluded therapeutic targeting by traditional antibody or small molecule inhibitors, making CRISPR-mediated editing a breakthrough strategy to unleash the full cytotoxic potential of T cells.

In this phase 1 clinical trial, twelve patients with highly metastatic, end-stage colorectal cancer were treated with autologous TILs engineered to lack functional CISH. The production process involved isolating tumor-infiltrating lymphocytes, applying CRISPR/Cas9 editing ex vivo to disable the CISH gene, and expanding the modified cells to over 10 billion before reinfusion. Remarkably, the infusion of these gene-edited immune cells was well tolerated, with no serious adverse events linked to the gene-editing procedure, highlighting the feasibility and safety of scaling this approach for clinical use.

Among the trial participants, several individuals experienced stabilization of their disease, indicating a halt in tumor progression. Notably, one patient achieved a complete response—the first time metastatic tumors disappeared completely and have not recurred in more than two years. This dramatic outcome provides compelling evidence that targeting intracellular checkpoints via gene editing can provoke powerful and durable anti-tumor immune responses. Such a complete remission in end-stage colorectal cancer is unprecedented, suggesting new therapeutic possibilities for patients with limited options.

Co-director of the Center for Genome Engineering, Dr. Branden Moriarity, explains the scientific rationale behind targeting CISH, underscoring that it functions intracellularly to impede T cell receptor signaling and cytokine responsiveness. Due to its intracellular localization, CISH was previously inaccessible to conventional checkpoint inhibitor therapies, typically designed to target extracellular proteins. Thus, the utilization of CRISPR/Cas9 allows for a permanent genetic "hardwiring" of checkpoint resistance into T cells, fundamentally transforming their capability to recognize and eliminate cancer cells.

Unlike traditional immune checkpoint inhibitors requiring repeated dosing, this gene-editing strategy imparts a sustained, one-time modification. According to Dr. Beau Webber, associate professor and a key member of the research team, this approach ensures that checkpoint blockade is embedded within the genome of the infused T cells themselves, potentially providing long-lasting therapeutic effects without the need for continuous administration. This permanent modification circumvents issues related to drug pharmacokinetics and patient compliance, offering a streamlined immunotherapeutic modality.

Integral to the success of this trial was the development of a robust, clinically compliant manufacturing process capable of producing large quantities of genetically engineered TILs without compromising cell viability or function. This milestone demonstrates the scalability of CRISPR-engineered cell therapies for solid tumors and sets the stage for more extensive clinical studies. The ability to generate billions of modified T cells provides the clinical muscle necessary to mount effective immune responses in the hostile tumor microenvironment.

Despite the optimism surrounding these findings, several challenges remain before this therapy can become widely accessible. Currently, the process is complex and resource-intensive, requiring sophisticated laboratory infrastructure and specialized expertise. The research team is actively pursuing strategies to streamline production protocols, reduce costs, and increase the rapidity of manufacturing. Additionally, efforts are focused on understanding the molecular and cellular mechanisms that contributed to the extraordinary complete response in the single patient to optimize patient selection and treatment regimens.

This trial exemplifies the extraordinary potential of synthetic biology and genome engineering to revolutionize cancer treatment. By directly manipulating intracellular immune checkpoints, scientists can now engineer immune cells with heightened precision and durability. The implications extend well beyond colorectal cancer, foreshadowing a new era of personalized, gene-edited immunotherapies targeting a broad spectrum of malignancies. The intersection of gene editing and immuno-oncology promises accelerated innovation, offering renewed hope to patients confronting devastating diseases.

The research was generously supported by funding from Intima Bioscience, a biotechnology company dedicated to advancing cellular therapies. The collaborative effort between academic investigators and industry partners underscores the importance of interdisciplinary cooperation to translate laboratory discoveries into transformative clinical solutions. As the field progresses, partnerships of this nature will be integral to overcoming scientific and logistical hurdles inherent to pioneering therapies.

Looking forward, the University of Minnesota Medical School and the Masonic Cancer Center remain dedicated to advancing this promising therapeutic frontier. Their commitment to high-impact translational research continues to position them as leaders in the battle against cancer, fostering an environment where innovative science rapidly crosses the barrier into clinical application. The outcomes of this trial represent a significant beacon of hope for patients with metastatic colorectal cancer and pave the way for future large-scale, multi-center studies to validate and expand upon these initial successes.

Subject of Research: People

Article Title: Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial

News Publication Date: 02-May-2025

Web References:

• The Lancet Oncology Article
• DOI: 10.1016/S1470-2045(25)00083-X

Keywords: Gene editing; Gene therapy; Cancer treatments; Cancer immunotherapy; Checkpoint therapy