Chronic Myeloid Leukemia Patients Undergoing Interferon Alpha Therapy Exhibit Normal Peripheral Blood Gamma Delta T Cells That May Be Expanded in Vitro to Generate Predominantly CD45RA-Positive Effector Memory Cells for Immunotherapy
Bibliographic record
Abstract
Abstract Abstract 3729 Comprising <10% of T lymphocytes in human blood, gamma delta T cells (GDTc) are cytotoxic immune surveillance cells that are an attractive option for adoptive immunotherapy. We have previously shown that healthy donor GDTc expanded in vitro are cytotoxic to EM-2 and K562 Ph+ leukemia cell lines but not to autologous peripheral blood mononuclear cells (PBMCs). Additionally, we have noted an oligoclonal expansion of GDTc in interferon alpha (IFNα) monotherapy treated chronic myeloid leukemia (CML) patients. The current study is aimed at elucidating the role that these cells play in the remission of IFNα-treated CML patients. Immunophenotyping of thawed PBMC samples from CML patients undergoing (IFN-ON) or who had discontinued IFNα monotherapy (IFN-OFF) revealed similar central CD45RA-CD27+ (5.7% ± 2.7%, mean ± standard error, n=6) and CD45RA-CD27- effector memory (3.7% ± 2.0%, n=6) GDTc pools compared to those from healthy age-matched donors (4.4% ± 1.2% and 4.7% ± 1.4% respectively, n=3), suggesting that GDTc pools are normal in these patients. However, differences approaching significance were observed between IFN-ON (n=3) and healthy controls (n=3), with IFN-ON exhibiting less CD45RA+CD27+ naïve GDTc (24.6% ± 6.7% compared to 48.2% ± 7.7%, p=0.08) and more terminally differentiated CD45RA+CD27- RA+ effector memory GDTc (66.4% ± 11.8% compared to 42.7 ± 7.3%, p=0.16). The percentage of GDTc expressing the activating Natural Killer cell receptor NKG2D was more variable and significantly lower in freshly thawed IFN-OFF patient samples (53.1% ± 4.6%, p=0.03) as compared to age-matched healthy donor controls (68.4% ± 1.5%). A similar trend was also observed between IFN-ON patients and healthy controls (IFN-ON 54.5% ± 8.8%, p=0.08). Although GDTc are typically difficult to recover and expand from cryopreserved PBMCs, we have developed a new protocol with which we can expand patient GDTc, potentially enabling the generation of therapeutic doses on demand. We achieved variable expansions of 41- to 9097-fold from patient samples over 21 days, with four of six patient cultures achieving over 100-fold GDTc expansion. Of these four cultures, two were from each patient group, suggesting that IFN-ON or –OFF status did not correlate with the ability of these cells to expand in vitro. Importantly, expanded GDTc were mostly terminally differentiated CD45RA+CD27- RA+ effector memory GDTc (52% ± 11.7%, n=6). Of the total GDTc population, 65.9% ± 4.6% expressed NKG2D (n=6), suggesting that our protocol can generate terminally differentiated cytotoxic GDTc. We are now investigating whether the cells expanded in vitro are the clonal GDTc population previously identified in our patients and whether these expanded cells are able to kill Ph+ leukemia cells. Our findings will be important not only for understanding the mechanism of IFNα-induced cure of the patients, but also for developing GDTc therapies for CML and other malignancies. Disclosures: Mustjoki: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".