Oncotarget recently published "Targeted lymphodepletion with a CD45-directed antibody radioconjugate as a novel conditioning regimen prior to adoptive cell therapy" which reported that Chimeric antigen receptor T cell therapies, and adoptive cell therapy in general, represent one of the most promising anti-cancer strategies.
In contrast to relatively non-specific chemotherapy-derived lymphodepletion, targeted lymphodepletion with radioimmunotherapy directed to CD45 may be a safer and more effective alternative to target and deplete immune cells. Here the authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11, labeled with two different beta-emitters 131Iodine and 177Lutetium, to investigate the effect of anti-CD45 RIT lymphodepletion on immune cell types and on tumor control in a model of adoptive cell therapy.
Treatment of mice with 3.7 MBq 131I-30F11 or 1.48 MBq 177Lu-30F11 safely depleted immune cells such as spleen CD4 and CD8 T Cells, B and NK cells as well as Tregs in OT I tumor model while sparing RBC and platelets and enabled E. G7 tumor control. These results support the application of CD45-targeted RIT lymphodepletion with a non-myeloablative dose of 131I-30F11 or 177Lu-30F11 antibody prior to adoptive cell therapy.
Dr. Dale L. Ludwig from Actinium Pharmaceuticals said, "Chimeric antigen receptor (CAR) T cell therapies, and adoptive cell therapy (ACT) in general, represent one of the most promising anti-cancer strategies."
It is unclear why some patients respond to treatment with adoptive cell therapies such as CAR-T, and others do not, though the tumor immune microenvironment is a likely contributor to variable effect of cell therapy in both hematologic and solid cancers.
Other cell types that contribute to an immunosuppressive tumor microenvironment that may negatively impact CAR-T efficacy include myeloid derived suppressor cells and tumor-associated macrophages.
Figure 7: Comparative tumor control by 177Lu-30F11 or 131I-30F11 antibody. Following E. G7 tumor engraftment, mice either received no treatment or were conditioned with 1.48 MBq 177Lu-30F11 or 3.7 MBq 131I-30F11 on Day 0 and then received 106 OT I CD8+ CD45.2 OVA reactive T cells on day 4. (A) 177Lu-30F11 and 131I-CD45-mediated targeted conditioning prior to adoptively transferred OT I T cells enabled control of E.G7 tumor growth. (B) Tumor size for individual mice in each group is displayed. OT I T cell persistence and expansion was confirmed in mice at the time of sacrifice. (C) Survival of mice in treated and in untreated control groups.
The CD45 antigen is found on all nucleated immune cells, with increased expression on mature lymphoid and myeloid lineages, leading to preferential depletion of mature immune cells compared to progenitor hematopoietic cells.
Importantly, immunomodulatory cells such as Tregs and MDSC express CD45 and are targets of lymphodepletion with a CD45-targeting antibody-radionuclide conjugate, potentially resulting in better engraftment, activation and persistence of the exogenously added CAR-T cells in patients.
Here the Oncotarget authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11, labeled with two different beta-emitters - 131I and 177Lutetium, to investigate the effect of anti-CD45 RIT lymphodepletion on immune cell types and on tumor control in a model of adoptive cell therapy.
"Here the Oncotarget authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11"
The Ludwig Research Team concluded in their Oncotarget Research Paper, "our data supports CD45 targeted RIT lymphodepletion with a non-myeloablative dose of 131I-30F11 or 177Lu-30F11 prior to adoptive cell therapy."
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DOI - https://doi.org/10.18632/oncotarget.27731
Full text - https://www.oncotarget.com/article/27731/text/
Correspondence to - Dale L. Ludwig - [email protected]
Keywords - anti-CD45 targeted lymphodepletion, radioimmunotherapy, adoptive cell therapy, 131Iodine, 177Lutetium
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