Seven Year Followup for Bystander Vaccine Therapy in Mantle Cell Lymphoma (MCL)

Background:

A Phase I study revealed that vaccination of cancer patients with irradiated autologous tumor cells and GM.CD40L bystander cells (engineered to secrete GM-CSF and express CD40L) is safe, recruits/activates dendritic cells, and elicits tumor-specific T cell responses. We report final results using this vaccine strategy in patients with MCL, an aggressive and incurable B-cell malignancy.

Methods:

After lymph node resection for autologous tumor harvest, 4-6 cycles of chemotherapy, and restaging (CT, endoscopy, bone marrow biopsy), patients with usable vaccine who achieved a PR or CR lasting 1 month were vaccinated x4 at 28-day intervals with IL-2 (0.5 x 10⁶ U SC BID x 14 d/cycle). Patients were monitored for toxicity, tumor response, tumor-specific immune responses, and median EFS/OS.

Results:

43 were enrolled, including 21 with relapsed MCL, 20 with int/high MIPI, and 6 with blastoid MCL. Twenty never received vaccine: 2 withdrew, 1 progressed prior to nodal harvest, 7 had insufficient or contaminated specimens, and 10 progressed/died during chemotherapy. The unvaccinated were older (68.4y vs 62.8y; p=.026) but otherwise did not differ significantly by stage, LDH, MIPI, de novo status, or number of prior treatments.

Among 23 treated, 10 had relapsed disease (median of 3 prior therapies), 10 had an int/high MIPI, and 2 had blastoid MCL. Pre-vaccination response following chemotherapy included 7 CR, 15 PR, and 1 SD. At 6 months after vaccination, 2 pts in PR had resolution of MRD within the bone marrow, 10 progressed (including 3 who progressed after 1-2 vaccines), and 11 had no change. Grade 3 toxicities were observed in three patients, and consisted of leukocytosis, neutropenia, and cough, none of which were attributed to vaccination. One patient remains in CR at 84 mo. A second who relapsed at 64mo remains without need for salvage therapy at 82 mo, suggestive of more indolent relapse post vaccination. Median EFS and OS are calculated from receipt of first vaccine. Median EFS is 9 mo, and median OS is 101 mo (median follow-up 81 mo).

DTH was not observed. Biopsy of vaccine sites revealed lymphocytic response in 62%, however, this was not correlated with EFS or OS. Increased IFN gamma post vaccination was observed in 76%, and accompanied by an increase in EFS (p=.06). Increased GMCSF post vaccination was observed in 89%, with a trend for improved survival among those with higher peak levels.

Conclusions:

Extended follow up continues to show a sustained benefit in regards to overall survival for patients with de novo (85% alive at 81 months) and relapsed MCL (median OS 25 months), and support therefore the need for further studies of vaccination strategies in the context of new immunotherapeutic agents that are improving the outcomes of MCL patients.

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