Lymphodepletion with CD45 Radioimmunotherapy as a Targeted Conditioning Regimen Prior to Adoptive Cell Therapy or CAR-T
Bibliographic record
Abstract
Lymphodepletion, using chemotherapy such as fludarabine and cyclophosphamide (flu/cy), is recognized as a critical step to create a favorable immune homeostatic environment in patients prior to adoptive cell therapy (ACT) or CAR-T. However, flu/cy is a cytotoxic and non-specific regimen that some patients may not be able to tolerate and is also correlated with cytokine release syndrome (CRS) and possibly neurotoxicity that can occur following CAR-T administration. Targeted lymphodepletion with radioimmunotherapy (RIT) directed to CD45 may be a safer and more effective alternative to target and deplete immune cells, including immune suppressor cells and those implicated in CRS. It may also reduce tumor burden since CD45 is overexpressed on most types of leukemia and lymphoma. The CD45 antigen is found on all nucleated immune cells with increased expression on mature lymphoid and myeloid lineages. Anti-CD45 RIT, 131I -apamistamab (BC8), is in a Phase III clinical trial as a myeloablative targeted conditioning regimen prior to allogeneic stem cell transplant in patients with active relapsed/refractory AML. Results from patients during dosimetry testing have shown that low non-myeloablative doses of 131I-apamistamab were able to safely induce transient lymphopenia; low dose anti-CD45 RIT may therefore be a promising targeted modality to effectively lymphodeplete prior to ACT. Studies were performed with an 131I-labeled anti-mouse CD45 antibody at varying non-myeloablative doses to investigate the effect of CD45-RIT targeted lymphodepletion on immune cell types and cytokine profiles. Following single dose administration of 50 to 200 mCi CD45-RIT, blood, spleen and bone marrow samples were collected from C57Bl/6 mice at 2 days and 4 days post-treatment for immunophenotyping and cytokine profiling. CD45-RIT was shown to mediate effective lymphodepletion of greater than 90% of lymphocytes (CD4 and CD8 T cells, CD19 B cells, and NK cells), but also CD4+, CD25+, FoxP3+ Tregs at doses that had negligible impact on bone marrow stem cells. Notably, in follow-up recovery studies, significant Treg suppression was sustained for at least 10 days post-lymphodepletion. CD45-RIT lymphodepletion also led to reductions in both MDSCs and other immune subsets. Concomitant with effective removal of cytokine sinks, levels of IFNg and IL-6 were unchanged in these non-tumor bearing mice. Although modest, trends for increased IL-15 levels in peripheral blood following targeted lymphodepletion were also observed. Results of CD45-RIT targeted conditioning prior to ACT in the E.G7/OT1 animal model will also be presented. These results demonstrate that targeted lymphodepletion with CD45 RIT can be achieved in a safe and effective manner supporting advancement to clinical testing of a single, low-dose, outpatient regimen (Iomab-ACT) that may effectively replace flu/cy conditioning prior to CAR-T.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".