RB-1355: Bypassing Lymphodepletion in Cellular Immunotherapy for Lymphomas

While chimeric antigen receptor (CAR) T-cell and natural killer (NK) cell therapies have revolutionized the hematologic oncology landscape, their clinical utility remains constrained by the requirement for lymphodepleting conditioning regimens and the immunosuppressive nature of the tumor microenvironment (TME). The metabolic and cytokine competition between endogenous and infused lymphoid cells often necessitates high-dose chemotherapy, which carries significant risks of cytopenia and secondary malignancies—particularly in frail or heavily pretreated patient populations.

RB-1355 represents a paradigm shift in cellular immunotherapy. By utilizing autologous macrophages—the primary effector cells of the innate immune system—this platform circumvents the traditional requirements for lymphodepletion. Unlike lymphoid-based therapies, RB-1355 functions independently of interleukin(IL)-7/IL-15 homeostatic signaling and demonstrates a unique resilience to myeloid-derived suppressor cells (MDSCs).^1,2

Beyond its favorable safety profile, RB-1355 addresses the challenge of antigen escape and heterogeneity in B-cell and T-cell lymphomas. Through a proprietary polarization process, these cells are "re-educated" into a potent pro-inflammatory phenotype capable of direct phagocytosis and subsequent antigen presentation. This transition from a "cold" to a "hot" TME triggers a robust, mutation-agnostic immune response, offering a scalable solution for patients who have exhausted standard lines of care.

In an interview with Targeted Oncology, Paolo Strati, MD, associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center and presenting author of the trial, explained the mechanism of action of RB-1355 and what it could offer to patients with B-cell and T-cell lymphomas.

One of the most striking findings is the lack of a requirement for lymphodepleting chemotherapy. Could you explain the biological mechanism that allows RB-1355 to engraft and expand effectively in a non-preconditioned host?

It's important to remind ourselves why we need lymphodepleting chemotherapy when we utilize other types of immune cells for cellular therapy, such as T cells and NK cells. So, the reason why we do need lymphodepleting chemo for T cells and NK cells is that when we infuse them, they tend to compete with endogenous T cells and NK cells, and they typically compete for cytokines and chemokines to be able to proliferate, for example, [IL-15] or [IL-7]. The other reason is that there's always a risk that [MDSC] may suppress the proliferation of T cells and NK cells. The advantage of macrophages as compared [with] T cells and NK cells is that they don't compete for cytokines and chemokines. Their antitumor activity is completely independent from those, and they're not inhibited by MDSC being myeloid cells themselves, so we don't have the need to utilize lymphodepleting chemo to deplete the endogenous pool of T cells and NK cells. And that represents major advantage in this trial, because most of the patients have received CAR T previously and multiple lines of chemo, and so we were able to avoid additional chemo that could increase the overall risk for secondary cancers. Moving forward, if we were able to expand the trial and run more patients, it will be very relevant for older patients and frail patients, who are unable to receive multiple lines of chemotherapy.

You observed responses in both B- and T-cell lymphomas. Given the diversity of these malignancies, how does RB-1355 achieve a mutation-agnostic response, and what specific "favorable immune changes" are being observed within the TME?

This is one of the key strengths of RB-1355. As a reminder, RB-1355 are autologous macrophages who are derived from circulating monocytes, and then they're exposed to a proprietary cytokine/chemokine cocktailwhich is able to repolarize macrophages to a more antitumoral phenotype. The advantage of this is the way macrophages work. They are natural antitumoral cells, and after exposure to this proprietary chemokine/cocktail called MACH-1 [Macrophage Activation Catalyst for Hyperactivation], they become more antitumoral. The activity is usually cytokine/chemokine-mediated, so it's really independent from the expression of antigens. In addition to that, for cases like B cells or T cell lymphomas, where antigens may be expressed at low density or be intracellular, macrophages they're doing their job, which is antigen presenting cells. To this regard, we have clearly observed in this trial that RB-1355 was able to increase the intratumoral proliferation of T cells and these were then able to eggress the tumor and go in the bloodstream. So even if the injection of RB-1355 was local, and the initial expansion of T cells in response to antigen presentation was local, it eventually became systemic.

For the patients in the trial who had previously failed CAR T therapy, what do we know about the phenotype of their T-cells, and why did RB-1355 succeed where prior cellular therapies failed?

There are always limitations in clinical trials where you try to address significant translational questions. One limitation is we were unable to retrospectively track back CAR T-cells that were received by patients on the trial for us to be able to characterize the phenotype, but we know from the literature that typically CAR T-cells in patients who relapse tend to be exhausted. One of the advantages of RB-1355, in addition to the direct antitumoral activity mediated by phagocytosis, is the true antigen presentation, and probably also through cytokine and chemokine mediated mechanism. Tumor associated macrophages can increase the concentration and the antitumoral function of intratumoral T cells, and overall induce a systemic T cell activation. And we have seen in preclinical models that RB-1355 was able to make T cells fitter. So we can make the assumption, though it's an assumption, because we cannot really track back in this trial retrospectively CAR T-cells, that maybe if there were any residual CAR T-cells from prior CAR T-cell exposure they were exhausted because of the tumor relapse, because of subsequent lines of treatment, but their fitness may actually have been improved by exposure to RB-1355, and we saw this very clearly in patient derived samples looking into T cell phenotype, they clearly became fitter once exposed to RB-1355.

How does the accelerated 1-week manufacturing timeline of RB-1355 fundamentally change your clinical management of "fast-progressing" refractory patients?

So that's an important change in manufacturing on the product that I do think will meaningfully clinically impact the management of this high-risk population. As a reminder, currently what's approved by the FDA in terms of cellular therapy for B cell lymphoma are autologous products, specifically autologous anti-CD19 CAR T, and the manufacturing requires genetic modification through a lentivirus in addition to multiple additional layers of safety control.

Typically, the median time from vein to vein is close to 17 days. But in this case, there's no requirement for genetic modification. It's just exposure to this proprietary chemokine cocktail, the vein-to-vein time may become as short as 7 days. Now clinically, this is very important in our practice; we all have patients whose progression is too fast for us to be able to wait for CAR T-cells to be manufactured. We do try to temporize as much as possible by utilizing holding treatments or bridging treatments, so additional systemic therapies or local therapies like radiation, given between leukapheresis and initiation of lymphodepleting chemo, but many times, the biology of those patients’ lymphoma is too aggressive, and patients sometimes because of that are unable to subsequently get access to their CAR T-cell product. So being able to minimize the vein-to-vein time to 1 week can definitely address this current clinical need.

REFERENCES

1.Strati P, Feldman T, Kidder K, et al. Intratumoral cellular therapy with autologous M1 SIRPαlow macrophages in NHL: clinical results from a FIH phase 1 study. Abstract presented at: 2026 Transplantation & Cellular Therapy Meetings of American Society for Transplantation and Cellular Therapy and Center for International Blood and Marrow Transplant Research; February 4-7, 2026; Salt Lake City, UT. Abstract 76.

2.First-in-human study finds novel immune cell therapy is safe and effective in advanced lymphoma. News release. MD Anderson Cancer Center. February 7, 2026. Accessed February 17, 2026. https://tinyurl.com/2b3uyxyw