At this year’s American Society of Clinical Oncology (ASCO) meeting, autologous cancer therapeutics developers described further clinical progress and continued to characterize the antitumor immune responses associated with vaccination. Accumulating clinical and immunologic evidence presented at this year’s ASCO meeting moved autologous cancer therapeutics further toward meeting the need for less toxic therapies.
Therapeutic vaccines such as Biovest’s BiovaxID could potentially be used to consolidate and extend first remissions in lymphoma patients induced by chemotherapy and antibodies with much less toxicity. Also, Dendreon reported use of its sipuleucel-T vaccine Provenge in the neoadjuvant prostate cancer setting.
In April Biovest sought marketing approval in Canada, and in May the firm announced its intention to file in Europe for BiovaxID in follicular non-Hodgkin lymphoma. EMA approval would establish BiovaxID as the first cancer vaccine available in Europe for lymphoma patients. The company has also announced that it expects to have discussions with the FDA prior to the end of 2012 and will seek FDA approval for BiovaxID for use as a consolidation agent.
At this year’s ASCO meeting, NCI investigators and collaborators at several institutions reported the use of Biovest’s BiovaxID vaccine as a nontoxic option for consolidation therapy to treat mantle cell lymphoma (MCL), which has a median survival of 3–5 years.
New highly aggressive chemotherapeutic regimens have improved the odds of surviving longer with follicular lymphoma, with some studies reporting median survival of over seven years. “But survival rates remain fairly dismal in older populations,” noted Carlos Santos, Ph.D., Biovest vp, product development and regulatory affairs.
Among these patients, use of anti-CD20 therapy like Roche’s Rituxan achieves complete remission in approximately 60–75% of treated patients. But currently, almost all patients who achieve a complete remission will relapse in about three years despite administration of maintenance or extended dosing with Rituxan.
Additionally older MCL patients, who represent the majority of those with MCL, often can’t tolerate harsh chemotherapeutic regimens. Moreover, with increasing age, improvements in overall survival (OS) decrease sharply.
At ASCO, Biovest and NCI-sponsored investigators reported clinical and immunologic findings from an 11-year follow-up of 26 MCL patients treated with BiovaxID following DA-EPOCH-Rituximab. Among MCL patients treated with BiovaxID, at a median follow up of 122 months, the median progression free survival (PFS) was 24 months and OS was 104 months. Most importantly, the PFS and OS advantage did not involve the use of toxic therapies to consolidate and extend first remissions.
In this study, investigators measured pre- and postvaccine immune responses (IR) including anti-Id and anti-KLH humoral responses as measured by ELISA, anti-KLH cellular responses measured by intracellular cytokine assay, and anti-tumor cellular responses as measured by cytokine induction and IFNγ ELISPOT. They found no association between OS and anti-KLH immune responses, anti-Id humoral responses (suggesting a high compatibility of BiovaxID with Rituxan), IFNγ ELISPOT, or antitumor TNFα or IFNγ response.
They did, however, report that an antitumor GM-CSF response was significantly associated with OS and time to next treatment (TTNT), suggesting that antitumor cellular immune response significantly delayed tumor growth. The antitumor GM-CSF response may serve, the authors said, as a surrogate biomarker for vaccine efficacy.
The results, consistent with other recent data showing that T-cell GM-CSF production is required to break tolerance against self-antigens, suggest that Id vaccines may one day safely and effectively prolong survival of MCL patients following Rituxan-based chemotherapy.
Dr. Santos commented that availability of an agent liked BiovaxID with T-cell activating properties, long persistence of effect, and a high degree of safety that complements Rituxan’s mechanism could potentially provide patients with a much-needed nonimmunosuppressive consolidation therapeutic option.
Wyndham H. Wilson, M.D., Ph.D., chief of the lymphoma therapeutics section at NCI and a co-author of the MCL study, told GEN that, “We found that among MCL patients treated with a hybridoma-based idiotype vaccine, patients who had T cells that produced GM-CSF when exposed to tumor antigen had a significantly longer survival and delayed time to next treatment compared to patients who did not have GM-CSF producing T cells. Interestingly, studies have shown that GM-CSF producing T cells are important for promoting autoimmunity, which is what we hope an antitumor vaccine will do. In the latter case, the autoimmunity is against a tumor antigen and not a normal cell.”
Biovest noted that the formal clinical development of BiovaxID began with the 1994 filing of an IND. The substantial span of this clinical development period has, according to the company, provided immunologic and clinical data from two Phase II studies and a randomized Phase III trial together with long-term follow up data.
The immunologic data collected and analyzed during the development period set a standard for cancer vaccine developers in terms of associating immunologic responses with clinical responses and identifying markers for the efficacy of therapeutic cancer vaccines.
Dendreon also provided immunological context for the efficacy of its Provenge prostate cancer autologous therapeutic vaccine. The vaccine was approved for use in some men with metastatic prostate cancer based on the results of the Phase III randomized Impact trial that demonstrated a more than four-month median improvement in overall survival compared to placebo.
Dendreon is evaluating Provenge as a neoadjuvant treatment for localized prostate cancer in the Phase II NeoACT open-label study. Patients received three infusions at approximately two-week intervals, beginning 6–7 weeks prior to radical prostatectomy (RP). Of 42 enrolled study patients, 38 received three infusions of Provenge, and 15 received a booster infusion.
Cellular composition, antigen presenting cell (APC) activation, cytokines, as well as T- and B-cell activation were profiled before and after each culture with PA2024, the fusion protein containing prostatic acid phosphatase used to generate Provenge. Additionally, a second analysis to assess the presence of lymphocytes in RP tissue following treatment with Provenge compared to prostate biopsy tissue prior to treatment was performed.
The studies showed increased T cells in the prostate RP tissue compared to pretreatment biopsies. Provenge also enhanced immune activity as demonstrated by increases in values of markers cited above and further resulted in enhanced immune system activation consistent with boosting of an immune response primed with the first infusion.
“It is encouraging that we are seeing T-cell infiltrates in the prostate tissue, in the interface between the normal and the cancer tissue,” said Mark Frohlich, M.D., Dendreon’s evp of R&D and CMO. “T cell infiltrates were not present prior to Provenge treatment, suggesting that Provenge is causing T cells to home to the prostate.”
“In prior studies we have shown antigen uptake into APCs, presentation of the peptides to T cells, and generation of T-cell and antibody responses,” Dr. Frohlich added. The missing piece, which this study provides, has been direct evidence that the generated immune responses attack the tumor.
GEN asked Dr. Frohlich if this more extensive immunologic data would have eased the path to FDA approval. “The increased data supporting the products mechanism of action would have been helpful,” he said. “In addition, we are now finding evidence for correlations between immune responses and clinical outcome. At the end of the day it’s the clinical story that drives FDA approval, but understanding mechanism of action will help us design even more potent immunotherapies for cancer.”
Dr. Wyndham shares that view: “I can say that at the end of the day the FDA always prefers direct measures of benefit and that is going to be survival. While it’s always good to have good correlative data, I see those as secondary, and as long as you have survival, these endpoints aren’t the drivers for approval.”
Nonetheless, as data about immunological mechanisms of action continue to accrue, Biovest, Dendreon, and other autologous vaccine developers will have information to guide the development of novel, less toxic cancer therapeutics.