Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma

Abstract

The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell-dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody-based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4(+) and CD8(+) antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses.

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

“…38,39 The IEGS33 scores of BL were slightly higher (mean SES D 0.6), suggesting that these lymphoma escape immunity through different pathways. 40,41 Low scores were also found in most but not all MCL 42,43 that included PD1 defects and autoimmunity in MZL. 44,45 In contrast, IEGS33 scores were significantly elevated in 73% of FL (mean SE D 1.4) and 78% of DLBCL (mean SES D 1.6) (Fig.…”

Vaccine Therapy for B-Cell Lymphomas: Next-Generation Strategies

“…We recently evaluated the effects of B-cell depletion induced by rituximab on immune responses to idiotype vaccines in a pilot clinical trial where 26 previously untreated patients with mantle cell lymphoma received 5 monthly cycles of autologous tumor-derived Id-KLH + GM-CSF vaccination following induction of clinical remission with dose-adjusted rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH-R). 10 Unexpectedly, despite rituximab administration, antibody responses against the carrier molecule KLH and Id were detected in 17 out of 23 (74%) and 7 out of 23 (30%) evaluable patients, respectively. The humoral responses were delayed and correlated with B-cell recovery that began approximately 6 months after completion of EPOCH-R and returned to baseline by 1 year in most individuals.…”

“…Thus, most humoral responses were detected after the fourth or fifth vaccination (7 to 8 months after completion of EPOCH-R), compared with after the first or second vaccinations in the follicular lymphoma study in which rituximab was not administered. 10,25 Additionally, in several patients, humoral responses were delayed 4 to 10 months after the last vaccination, suggesting that priming may occur at low B-cell levels, whereas detectable antibody titers require adequate B-cell expansion. In contrast, vigorous CD4 + and CD8 + antitumor and KLH T-cell responses were not delayed and were induced in 20 out of 23 (87%) and 23 out of 23 (100%) patients, respectively, in the absence of circulating B cells.…”

“…In contrast, vigorous CD4 + and CD8 + antitumor and KLH T-cell responses were not delayed and were induced in 20 out of 23 (87%) and 23 out of 23 (100%) patients, respectively, in the absence of circulating B cells. 10 Professional antigen-presenting cells such as dendritic cells may effectively present antigen to T cells in the absence of B cells. Although we did not measure B cells within lymphatic tissues, other studies have shown that rituximab also depletes B cells in lymph nodes, spleen, and bone marrow in animals 26,27 and humans.…”

“…8,9 Third, idiotype vaccination can potentially induce polyclonal antibody and T-cell responses and therefore may reduce the appearance of immune escape variants. 10 …”