Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
In trying to understand what constitutes an effective immune response, researchers find it’s all about T cells.
A key hurdle in the development of cancer immunotherapies has been the absence of biomarkers that indicate the efficacy and kinetics of antitumor immune responses. The identification of immune response biomarkers may also predict which patients are most likely to benefit from active immunotherapies.
As data accumulates, a clearer picture of the immune correlates for an effective anti-tumor response is emerging. Cancer immunotherapy involves stimulation of the immune system with reagents such as vaccines, T cells, or cytokines. These agents stimulate antitumor response either by increasing effector cell numbers or by producing one or more soluble mediators such as lymphokines. They may also act to decrease suppressor mechanisms, causing tumor cells to increase their immunogenicity and making them more susceptible to immunologic defenses.
To date, FDA has approved one autologous therapeutic cancer vaccine for certain men with metastatic prostate cancer, Dendreon’s Provenge (sipuleucel-T). The vaccine consists of autologous peripheral blood mononuclear cells (PBMCs) including antigen presenting cells (APCs) that have been activated ex vivo with a recombinant fusion protein, PA2024. The fusion protein consists of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF).
Dendreon presented data at the American Society of Clinical Oncology’s “2012 Genitourinary Cancers Symposium” this February on clinical results and mechanism of action studies among prostate cancer patients treated with Provenge. The company reported Phase II data from its NeoACT study, undertaken to provide understanding of Provenge’s immunologic effects.
The open-label trial included 42 patients and analyzed immune responses to sipuleucel-T among patients with localized prostate cancer. Patients received three infusions of Provenge at approximately two-week intervals beginning 6–7 weeks prior to radical prostatectomy (RP) surgery.
The researchers concluded that “neoadjuvant sipuleucel-T resulted in robust immune system activation that included antigen presenting cells, memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile.”
The company also reported immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer. In this study, immunohistochemical (IHC) analysis showed that sipuleucel-T treatment resulted in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. The data suggests that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. The company and others commenting on this and other immune response data say that “Provenge should be studied in earlier stages of disease, when patients have less tumor burden.”
Abramson Cancer Center
Researchers at the Perelman School of Medicine and the Abramson Cancer Center at the University of Pennsylvania reported last month that a short course of vaccination with an anti-Her2 dendritic cell vaccine made partly from the patient’s own cells triggered complete tumor eradication in nearly 20% of women with ductal carcinoma in situ (DCIS). Brian Czerniecki, M.D., Ph.D., surgical director of the immunotherapy program for the Abramson Cancer Center, enrolled 27 women with Her2-positive DCIS in the vaccine study.
The investigators isolated lymphocytes from patients’ blood, then activated dendritic cells, priming them with small segments of the Her2/neu protein. Each patient then received four injections one week apart. After two weeks patients had surgery to remove any remaining disease, the standard of care for DCIS patients.
At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease. In the 22 subjects with residual DCIS, Her2/neu expression was eradicated in 11 (50%) of them, and reduced by 20 percent or more in another two. “We are continuing to see this pattern in our second, ongoing trial,” Dr. Czerniecki says. When comparing estrogen receptor (ER) negative with ER-positie DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER-negative subjects compared with 5.9% in ER-positive patients.
In analyzing patient immune responses, the investigators found that 85% had Her2-reactive CD4 and CD8 T cells. This suggests that the patients developed a robust and relatively complete immune response after vaccination. Some patients maintained their immune responses for as long as 52 months.
“Previous vaccines targeted tissue antigens that were expressed on the cancer cells but were not necessary for tumor survival,” Dr. Czerniecki noted. “So a vaccine response would cause the tumor to just stop expressing the antigen and the tumor would be fine. Here we’re going after Her2/neu, which is critical for survival of early breast cancers. If we knock it out with the immune response, we cripple the tumor cells.”
Regarding Herceptin, Dr. Czerniecki told GEN, “Herceptin is an anti-Her2/neu antibody. This autologous vaccine activates anti-Her2 CD4, CD8, and antibodies.” Because of the nature of the vaccine, patients’ immune responses are maintained against Her2. “Herceptin lasts few months and is gone; it is only antibody therapy,” Dr. Czerniecki explained.
“Eventually if we get this working a little better with some combinations such as vaccine plus trastuzumab or lapatinib, this could be a standalone therapy alternative, allowing the immune response to last longer,” Dr. Czerniecki added. “Ultimately the goal is to prevent disease recurrence and avoid radiation therapy.”
Last December Biovest International presented results of an 11-year, Phase II study it conducted with NCI testing its BiovaxID® in the treatment of mantle cell lymphoma (MCL). Study results showed that BiovaxID active immunotherapy following treatment with rituximab combination chemotherapy induced nearly universal immune responses. These responses, which strongly correlated with overall survival (OS) in treated patients, primarily consisted of tumor-specific T-cell immune responses.
BiovaxID comprises a protein isolated from each patient’s tumor combined with a carrier protein and administered with GMCSF. It stimulates the immune system to target a protein (idiotype) exclusively expressed on malignant B cells.
As part of the clinical development of BiovaxID, in 2000 the NCI began the Phase II trial in MCL patients who received rituximab-combination chemotherapy (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone, rituximab; EPOCH-R) prior to vaccination with BiovaxID to determine the impact of severe B-cell depletion on vaccine-induced immune responses.
With 122 months of median follow-up, the median overall patient survival in this study was 104 months. The investigators reported a significant association between T-cell immune responses (measured by antitumor, post-vaccine T-cell cytokine induction) and overall survival. The median overall survival in patients who did not develop or developed a below-median vaccine-induced T-cell response was 79 months at the time of follow-up.
“Our clinical trial experience with BiovaxID immunotherapy demonstrates that vaccination of lymphoma patients results in a broad spectrum antitumor immune response involving both cellular and humoral immune repertoires,” Carlos Santos, Ph.D., Biovest’s svp told GEN. “Further, randomized clinical trial data demonstrate that vaccination effectively extends remission duration lymphoma.
Dr. Santos emphasized that Biovest’s 11-year follow up with these vaccines “now shows that not only does vaccination provide clear improvements in remission duration but also that these vaccines may fundamentally alter tumor kinetics over many years. T-cell immune responses primed by Id vaccination in turn change tumor growth such that patients survive with lower disease aggressiveness.”
Moreover, he said, clinicians now for the first time may offer patients therapies that may truly add benefit without also adding significant risk, changing the risk/benefit equation in cancer treatment in ways even a decade ago would have seemed far beyond reach.
Patricia F. Dimond, Ph.D. (firstname.lastname@example.org), is a principal at BioInsight Consulting.