Bystander-Based Immunotherapy for Patients with Mantle Cell Lymphoma (MCL): Proof of Principle.

Background: A Phase I study showed that vaccination of cancer patients with autologous tumor cells and GM.CD40L bystander cells (engineered to express GM-CSF and CD40L) is safe, can recruit and activate dendritic cells, and can elicit tumor-specific T cell responses. Our goal was to test this bystander-based vaccine strategy in patients with mantle cell lymphoma (MCL).

Methods: Patients with de novo or relapsed Stage II–IV MCL underwent lymph node resection to harvest autologous tumor cells. Patients received induction chemotherapy (CHOP + Rituxan, hyper-CVAD + Rituxan, or other appropriate chemotherapy for those patients that relapsed after previous chemotherapy) and then underwent restaging with CT scans, upper and lower endoscopy, and bone marrow biopsy. Patients for whom the Cell Therapy Lab was successful in producing usable vaccine and who had achieved a partial or complete response (PR or CR) after cytoreductive chemotherapy-Rituxan were then vaccinated. Patients received 4 intradermal vaccine injections (irradiated autologous tumor cells plus GM.CD40L bystander cells) at 28-day intervals. Patients were monitored for toxicity, tumor response (including flow cytometry, FISH, and PCR for t(11;14) of bone marrow biopsies), and tumor-specific immune responses (DTH and ELISPOT assays).

Results: The protocol was opened for accrual on 07/27/04. Since then, 35 patients have been enrolled. Fifteen (15) patients are off the protocol and never received vaccine: 2 withdrew consent prior to tumor harvest, 1 progressed rapidly and became too ill for surgery, 1 did not have MCL in the harvested tissue, 3 had contaminated specimens, 6 progressed during chemotherapy and never became eligible for vaccine, and 2 died while on chemotherapy. Three (3) patients progressed during the course of vaccine therapy and were withdrawn from the study for treatment with further chemotherapy. Thirteen (13) patients all had successful tumor harvest and vaccine production, responded to cytoreductive chemotherapy, and proceeded with vaccine therapy: Six (6) of these had Progressive Disease after vaccine, 5 had Stable Disease, and 1 had a Complete Response by PCR molecular analysis of minimal residual disease in the bone marrow. One (1) patient had successful tumor harvest and responded well to cytoreductive chemotherapy, and is now receiving vaccine injections. Three (3) patients had successful tumor harvest and are still receiving cytoreductive chemotherapy. The vaccine (bystander cells + autologous tumor cells, followed by ultra-low-dose IL-2) has been well tolerated to date. Accrual has been slower than anticipated, and not all enrolled patients have proceeded to vaccine therapy, either due to failed vaccine production or disease progression and death prior to the vaccine phase of the study. Serum, PBMCs, and biopsies are being collected prospectively for immune monitoring and other correlative studies. Preliminary data show that T cell unresponsiveness in vitro (cytokine release in ELISPOT assays) can be reversed by vaccine treatment in vivo.

Conclusions: This Phase II study is still open for enrollment. It is too early to evaluate the clinical and immunological impact of this GM.CD40L bystander-based vaccine on patients with MCL, but preliminary results show a complete molecular response in the bone marrow of at least one patient previously treated for MCL, providing impetus for ongoing accrual.