Cancer immunotherapy Dillman, Robert O
Cancer biotherapy & radiopharmaceuticals
26, Številka:
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Journal Article
Recenzirano
Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During the past 25 years, 17 ...immunologic products have received regulatory approval based on anticancer activity as single agents and/or in combination with chemotherapy. These include the nonspecific immune stimulants BCG and levamisole; the cytokines interferon-α and interleukin-2; the monoclonal antibodies rituximab, ofatumumab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab; the radiolabeled antibodies Y-90 ibritumomab tiuxetan and I-131 tositumomab; the immunotoxins denileukin diftitox and gemtuzumab ozogamicin; nonmyeloablative allogeneic transplants with donor lymphocyte infusions; and the anti-prostate cancer cell-based therapy sipuleucel-T. All but two of these products are still regularly used to treat various B- and T-cell malignancies, and numerous solid tumors, including breast, lung, colorectal, prostate, melanoma, kidney, glioblastoma, bladder, and head and neck. Positive randomized trials have recently been reported for idiotype vaccines in lymphoma and a peptide vaccine in melanoma. The anti-CTLA-4 monoclonal antibody ipilumumab, which blocks regulatory T-cells, is expected to receive regulatory approval in the near future, based on a randomized trial in melanoma. As the fourth modality of cancer treatment, biotherapy/immunotherapy is an increasingly important component of the anticancer armamentarium.
In a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor ...cell vaccines (TCV). Both vaccines presented antigens from cell-renewing autologous tumor cells. The current analysis was performed to better understand the immune responses induced by these vaccines, and their association with survival.
110 proteomic markers were measured at a week-0 baseline, 1 week before the first of 3 weekly vaccine injections, and at week-4, 1 week after the third injection. Data was presented as a deviation from normal controls. A two-component principal component (PC) statistical analysis and discriminant analysis were performed on this data set for all patients and for each treatment cohort.
At baseline PC-1 contained 64.4% of the variance and included the majority of cytokines associated with Th1 and Th2 responses, which positively correlated with beta-2-microglobulin (B2M), programmed death protein-1 (PD-1) and transforming growth factor beta (TGFβ1). Results were similar at baseline for both treatment cohorts. After three injections, DCV-treated patients showed correlative grouping among Th1/Th17 cytokines on PC-1, with an inverse correlation with B2M, FAS, and IL-18, and correlations among immunoglobulins in PC-2. TCV-treated patients showed a positive correlation on PC-1 among most of the cytokines and tumor markers B2M and FAS receptor. There were also correlative changes of IL12p40 with both Th1 and Th2 cytokines and TGFβ1. Discriminant analysis provided additional evidence that DCV was associated with innate, Th1/Th17, and Th2 responses while TCV was only associated with innate and Th2 responses.
These analyses confirm that DCV induced a different immune response than that induced by TCV, and these immune responses were associated with improved survival. Trial registration Clinical trials.gov NCT004936930 retrospectively registered 28 July 2009.
GM-CSF drives the differentiation of granulocytes and monocyte/macrophages from hematopoietic stem cell progenitors. It is required for differentiating monocytes into dendritic cells (DC). Although ...approved for recovery of granulocytes/monocytes in patients receiving chemotherapy, G-CSF is preferred. Enthusiasm for GM-CSF monotherapy as a melanoma treatment was dampened by two large randomized trials. Although GM-CSF has been injected into tumors for many years, the efficacy of this has not been tested. There is a strong rationale for GM-CSF as a vaccine adjuvant, but it appears of benefit only for strategies that directly involve DCs, such as intratumor talimogene laherparepvec and vaccines in which DCs are loaded with antigen
and injected admixed with GM-CSF.
Because of the recent success of monoclonal antibody checkpoint inhibitors, and the disappointing results of most therapeutic cancer vaccine trials, it has been questioned whether there is any ...potential role for such products going forward. In my opinion the answer is "yes" based on the following: 1 there is a persistent unmet clinical need because the majority of patients do not benefit from anti-checkpoint therapy, 2 there is evidence that not all patients make immune responses to their tumors, 3 there is evidence that immune responses to autologous tumor antigens can be induced by patient-specific vaccines, 4 there is clinical evidence from the pre-checkpoint era that suggests survival can be positively impacted by such patient-specific vaccines, and 5 the 2 available therapeutic vaccines that have received regulatory approval are quite limited in terms of their therapeutic benefit.
A promising personal immunotherapy is autologous dendritic cells (DC) loaded ex vivo with autologous tumor antigens (ATA) derived from self-renewing autologous cancer cells. DC-ATA are suspended in ...granulocyte-macrophage colony stimulating factor at the time of each subcutaneous injection. Previously, irradiated autologous tumor cell vaccines have produced encouraging results in 150 cancer patients, but the DC-ATA vaccine demonstrated superiority in single-arm and randomized trials in metastatic melanoma. DC-ATA have been injected into more than 200 patients with melanoma, glioblastoma, and ovarian, hepatocellular, and renal cell cancers. Key observations include: 1 greater than 95% success rates for tumor cell cultures and monocyte collection for dendritic cell production; 2 injections are well-tolerated; 3 the immune response is rapid and includes primarily TH1/TH17 cellular responses; 4 efficacy has been suggested by delayed but durable complete tumor regressions in patients with measurable disease, by progression-free survival in glioblastoma, and by overall survival in melanoma.
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Background: Seizures are not an uncommon presenting symptom of glioblastoma (GBM), and may occur following surgery for GBM. Such seizures typically can be controlled with anti-epileptics, and ...the risk of seizures seems to decrease after concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ). However, the risk of seizures theoretically might be increased in association with a therapeutic intervention designed to enhance local inflammation at the GBM site. 33% of patients experienced one or more seizures as a treatment-emergent-adverse-event (TEAE) during a phase II clinical trial of AV-GBM-1, patient-specific dendritic cell vaccines that consist of autologous dendritic cells loaded with autologous tumor associated antigens derived from a short-term culture of self-renewing tumor cells, that were injected subcutaneously for up to six months after recovery following concurrent RT/TMZ (Bota DA et al. 2021 Society for Immunotherapy of Cancer (SITC) late-breaking abstract #952, 2021 Society of Neuro-Oncology abstract #CTIM-33). A literature search was conducted to determine reported rates of seizures as TEAE in primary GBM patients in clinical trials. Methods: Phase III trials of systemic treatment of primary GBM, and published during 2005 to 2021, were identified by searches of clinicaltrials.gov and PubMed. Published reports were reviewed for data describing the frequency of seizures reported as TEAE in text and/or summary tables. Only trials that had at least 50 patients in a standard treatment arm of surgical resection, RT/TMZ and maintenance TMZ were included. Chi square test was used to compare proportions of patients experiencing seizures in these trials. Results: Eight such randomized trials were identified. Five trials did not mention seizures as TEAE. One trial provided data only for grade 3 and 4 events: 13/229 (5.7%). The other two trials reported all seizures regardless of grade, but were limited to patient populations with O
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-methylguanine-DNA-methyltransferase promoter methylation in one, and epidermal growth factor receptor amplification in the other. The rates of seizures in those two trials were much lower than the 19/57 (33.0%) reported with AV-GBM-1: 28/258 (10.9%, p < 0.0001), and 69/372 (15.4%, p = 0.0136). Conclusions: The frequency of seizures that occur in GBM patients receiving standard RT/TMZ is not well-documented in publications of large, randomized trials. AV-GBM-1 may be associated with a higher rate of seizures because of treatment-induced inflammation at the tumor site, but a randomized trial would be needed to determine this.
Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) ...Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.
Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.
Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.
AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.
NCT, NCT03400917 , Registered 10 January 2018.
Belagenpumatucel-L is a nonviral gene-based allogeneic tumor cell vaccine that demonstrates enhancement of tumor antigen recognition as a result of transforming growth factor beta-2 inhibition.
We ...performed a randomized, dose-variable, phase II trial involving stages II, IIIA, IIIB, and IV non-small-cell lung cancer patients. Each patient received one of three doses (1.25, 2.5, or 5.0 x 10(7) cells/injection) of belagenpumatucel-L on a monthly or every other month schedule to a maximum of 16 injections. Immune function, safety, and anticancer activity were monitored.
Seventy-five patients (two stage II, 12 stage IIIA, 15 stage IIIB, and 46 stage IV patients) received a total of 550 vaccinations. No significant adverse events were observed. A dose-related survival difference was demonstrated in patients who received > or = 2.5 x 10(7) cells/injection (P = .0069). Focusing on the 61 late-stage (IIIB and IV) assessable patients, a 15% partial response rate was achieved. The estimated probabilities of surviving 1 and 2 years were 68% and 52%, respectively for the higher dose groups combined and 39% and 20%, respectively, for the low-dose group. Immune function was explored in the 61 advanced-stage (IIIB and IV) patients. Increased cytokine production (at week 12 compared with patients with progressive disease) was observed among clinical responders (interferon gamma, P = .006; interleukin IL -6, P = .004; IL-4, P = .007), who also displayed an elevated antibody-mediated response to vaccine HLAs (P = .014). Furthermore, positive enzyme-linked immunospot reactions to belagenpumatucel-L showed a correlation trend (P = .086) with clinical responsiveness in patients achieving stable disease or better.
Belagenpumatucel-L is well tolerated, and the survival advantage justifies further phase III evaluation.
Hepatic metastases from melanoma are usually associated with recurrence and short survival, even in patients with a solitary metastasis. Two patients, one with melanoma of unknown primary and one ...with ocular melanoma, underwent resection of a solitary liver metastasis followed by treatment with eltrapuldencel-T, a patient-specific therapeutic vaccine consisting of autologous dendritic cells loaded with antigens from irradiated melanoma cells obtained from an autologous tumor cell line. Following surgical resection, the ocular melanoma patient remained progression free for more than 4.5 years and was known to be alive more than 8.5 years later, while the other patient, who previously had experienced lung and small bowel metastases, has remained disease free and is alive more than 12 years later. These two cases illustrate how immunotherapies designed to induce immune responses to tumor-associated antigens (TAA), as opposed to releasing previously existing responses to TAA that have been suppressed, may also enhance long-term disease control and survival.
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