PHASE I/II CLINICAL TRIAL OF AN ACTIVATED WHOLE TUMOR CELL VACCINE FOLLOWED BY TRANSFER OF IMMUNE T CELLS IN PATIENTS WITH MANTLE CELL LYMPHOMA
Bibliographic record
Abstract
Introduction: We report interim results of a CpG-activated whole tumor cell vaccine for patients with newly diagnosed Mantle Cell Lymphoma (MCL). This phase I/II trial (NCT00490529) had the primary end points of safety and freedom from minimal residual disease (MRD) at 1 year post autologous stem-cell transplant (ASCT). Secondary end points include time to treatment failure (TTF) from initial chemotherapy, overall survival (OS), and T cell immune response. Methods: Prior to treatment, patient-specific vaccines were made by activating freshly collected tumor cells with PF-3512676 (CpG) followed by radiation (200 Gy). Patients with a partial or complete response after standard immunochemotherapy received three subcutaneous injections with the vaccine product together with additional CpG (18 mg). T-cells were collected by leukapheresis after the last vaccine and cryopreserved. The day after an ASCT, the T-cell product was infused and a 4th vaccination was given. A 5th booster vaccination was given ~3 months post ASCT. Blood samples were collected at various time points for measurement of anti-tumor immune responses and for detection of MRD by VDJ high throughput sequencing of blood mononuclear cells (ClonoSeq™). Results: Between April 2008 and August 2016, 65 patients were enrolled and 43 patients have completed ASCT and are included in the safety analysis. The CpG MCL vaccine was well tolerated. The most common toxicity was grade I/II erythematous rash at the injection site (98%), and no unexpected toxicities were seen before or after ASCT. 34 patients are at least 1 year post ASCT and included in the primary analysis. 31 (91%) patients were MRD negative at the previously validated threshold (1 MCL clone per 10,000 input genome equivalents of DNA). MRD negativity at 1-year post ASCT predicted longer subsequent remission duration (p < 0.0001) and survival (p = 0.0021). Lower levels of MRD down to 1 per million were occasionally detected but were not associated with relapse or survival. Median TTF and OS have not been reached (NR) with an average follow-up of 4.91 years. By comparison a contemporaneous cohort of similar patients with MCL who received the same ASCT at our institution, but with no vaccine, have a median TTF of 4.03 years (p = 0.164). Analysis of the vaccine characteristics revealed that patients whose tumor cells demonstrated CpG-induced elevation of PD-L1 had significantly worse TTF (2.4 years vs NR, p = 0.0037) and OS (3.2 years vs NR, p = 0.0042). We also detected tumor-specific CD4+ and CD8+ T cell immune responses following vaccination. Conclusion: The addition of a CpG-activated, autologous tumor cell vaccination and adoptive immune T-cell product to standard therapy for MCL is feasible and safe. At this interim analysis, vaccinated patients had freedom from MRD at 1 year post transplant that surpasses previously reported rates. Keywords: B-cell lymphoma; mantle cell lymphoma (MCL); minimal residual disease (MRD)
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".