Abstract 3808: 225Ac-CD33 Radioimmunotherapy potently increases the sensitivity of resistant acute myeloid leukemia lines to the Bcl-2 inhibitor venetoclax by mediating a reduction in cellular Mcl-1 levels
Bibliographic record
Abstract
Abstract Acute myeloid leukemia (AML) is a complex hematological disease often occurring in older patients. While a number of new targeted therapies have been recently approved, patient outcomes remain poor. In the US, about 19,520 new cases AML occur annually and approximately 10,670 will die from the disease. Venetoclax is a promising new targeted therapy that is under regulatory review in the US for use in combination with a hypomethylating agent (HMA) or with low-dose cytarabine (LDAC) for the treatment of newly diagnosed patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Recently, several studies have demonstrated that increased expression of Mcl-1 is a mediator of resistance to venetoclax in AML and other hematologic malignancies. Indeed, significant up-regulation of Mcl-1 has been reported in patients with relapsed/refractory AML and venetoclax treatment itself has been shown to increase Mcl-1 levels tumor cell lines. 225Ac-lintuzumab is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. 225Ac-lintuzumab enables delivery of the potent alpha emitting warhead 225-actinium (T1/2 = 10 days; high linear energy transfer = 6.83 MeV; and short path length = 40-100 μm or about 3-5 cell diameters) directly to tumor cells. This elicits DNA cluster breaks and double strand breaks to kill within a short radius, thereby limiting damage to normal tissue. In this study, we demonstrate that 225Ac-lintuzumab is capable of dramatically enhancing the potency of venetoclax when used in combination in both venetoclax sensitive and resistant AML cell lines. AML lines U937 and OCI-AML3 are Mcl-1 positive AML lines which are highly resistant to venetoclax (IC50 > 1 μM). While treatment of these lines with single agent venetoclax at 500 nM was ineffective at suppressing tumor cell growth in either model, the combination of 40 nCi 225Ac-lintuzumab plus 500 nM venetoclax induced a statistically significant increase tumor cell killing in vitro. While 225Ac-lintuzumab can directly effect tumor cell killing by multiple mechanisms, we investigated the potential for 225Ac-lintuzumab-directed DNA damage to suppress Mcl-1 levels as a potential mechanism of enhancing the potency of venetoclax in these models. Cell lines were incubated with titrations of 225Ac-lintuzumab prior to analysis of Mcl-1 protein by ELISA. In both cell lines, treatment with 225Ac-lintuzumab lead to a significant depletion of Mcl-1 levels in cells. This supports a mechanistic basis of Mcl-1 suppression when 225Ac-lintuzumab is used in combination with venetoclax to increase the potency of resistant AML cells to the Bcl-2 inhibitor. Results of in vivo tumor xenograft studies will also be presented. Citation Format: Ravendra Garg, Eileen Geoghegan, Kevin J. Allen, Wojciech Dawicki, Ekaterina Dadachova, Dale L. Ludwig. 225Ac-CD33 Radioimmunotherapy potently increases the sensitivity of resistant acute myeloid leukemia lines to the Bcl-2 inhibitor venetoclax by mediating a reduction in cellular Mcl-1 levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3808.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".