Vanessa Caceres

A plenary session held November 15 at the Society of Neuro-Oncology&rsquo;s (SNO) 2014 Annual Meeting in Miami Beach focused on immunotherapy&rsquo;s promise as well as its challenges as a treatment for patients with brain cancer.

Immunotherapy is coming of age not only in general oncology, but also in neuro-oncology, noted SNO President David Reardon, MD, one of four experts speaking at the session: &ldquo;When you think of immunotherapy in neuro-oncology, there&rsquo;s always been some hesitancy in applying it.&rdquo;

Reardon, clinical director, Center for Neuro-Oncology at the Dana-Farber Cancer Institute, explained that this is because of previous research that appeared to show the central nervous system has immune privilege; however, &ldquo;new evidence suggests that this might not be true and that there is a dynamic interaction with the peripheral systemic immune system and the central nervous system,&rdquo; giving immunotherapy the potential to treat neuro-oncology patients.

Vaccines under investigation within the subspecialty can be classified into three categories: tumor lysates (such as DCVax L, HSPPC-96, and Allogeneic GBM stem cell line), tumor associated antigens (ICT-107, SL-701, and IMA950), and tumor-specific antigens (rindopepimut, CMV, and NeoVax). Reardon said that the immunotherapies that are furthest along are DCVax-L, HSPPC-96, and rindopepimut, which are all in randomized phase III trials. Nearly all of the research into these treatments is ongoing, with the exception of ICT-107, which has a completed randomized phase II trial, and NeoVax, which will be studied in a phase I trial that will begin soon.

Other immunotherapeutic approaches include CAR T-cell therapies, which, Reardon said, have been shown to have a dramatic effect in patients who have failed on other therapies. &ldquo;This takes T cells out, engineers them ex vivo, and gives the back to patients.&rdquo;

Despite the positive findings related to immunotherapy and neuro-oncology, however, physicians and patients have some challenges to overcome, said Reardon. &ldquo;These tumors adapt themselves to exploit many different mechanisms of suppressing immune reactivity.&rdquo;

Additionally, patients with brain cancer tend to be significantly immunosuppressed. &ldquo;Very dramatically, we see multiple mechanisms the tumor has exploited to generate a protective shield and protect itself from the immune system. These are the challenges that confront us using immunotherapy,&rdquo; Reardon concluded, noting that it is likely that immunotherapy will be used in neuro-oncology in combination with other therapies, including cytotoxic therapies.

In another plenary session talk, John Sampson, MD, PhD, said the current focus on immunotherapy is a &ldquo;paradigm shift&rdquo; within cancer and that the idea of immune privilege does not seem as certain as it did in the past. &ldquo;The idea that the bloodbrain barrier is an absolute barrier is not true,&rdquo; he said.

Sampson, the Dr. Robert H. Wilkins and Gloria Wilkins Professor of Neurosurgery and interim chief, Division of Neurosurgery, at Duke University Medical Center, provided several areas where immunotherapy can intervene in treatment: for the release of cancer cell antigens; cancer antigen preservation, priming, and activation; the trafficking of T cells to tumors; the infiltration of T cells into tumors; the recognition of cancer cells by T cells; and the killing of T cells.

The specificity of treatment that occurs with immunotherapy raises one concern, Sampson noted: &ldquo;As we go to more tumor-specific targets, it&rsquo;s wonderful, but we&rsquo;re not getting to the heterogeneity of the disease.&rdquo;

Future research will need to pinpoint how to optimize vaccine strategies for neuro-oncology patients, Sampson said.

The plenary session also included presentations from Gordon J. Freeman, PhD, associate professor of medicine, Harvard Medical School, who gave an overview of immune checkpoint biology and therapeutic translation, and a talk from Stephen Gottschalk, MD, director, Basic & Translational Research Division, Texas Children&rsquo;s Cancer Center, on the topic of T cells as therapeutics for glioblastoma.

Articles

A plenary session held November 15 at the Society of Neuro-Oncologyâ€™s (SNO) 2014 Annual Meeting in Miami Beach focused on immunotherapyâ€™s promise as well as its challenges as a treatment for patients with brain cancer.

Immunotherapyâ€™s Potential in Neuro-Oncology

According to data from a phase I study, the oncolytic virus Delta-24-RGD can infect, replicate, and kill glioma cells in patients. This research was presented at the 2014 Society for Neuro-Oncology (SNO) Annual Meeting in Miami.

Delta-24-RGD is a novel replication-competent, tumor-selective, oncolytic adenovirus that has enhanced infectivity, according to lead author Frederick F. Lang, MD, who presented the data. After preclinical studies demonstrated promising results, researchers began a first-in-human phase I study to assess the virus&rsquo;s capacity to replicate in human gliomas.

Study objectives included a focus on the maximum-tolerated dose of Delta-24-RGD administered directly into the tumor or via the post resection catheter, determine local and systemic toxicity of the virus after intracranial injection, and determine the biological effects at the molecular level with the examination of post-treatment tumor specimens.

&ldquo;We wanted to show it could do what it was meant to do at a biological level,&rdquo; said Lang, who is a professor and director of clinical research in the Department of Neurosurgery at The University of Texas MD Anderson Cancer Center.

The study assigned 37 patients with recurrent high-grade gliomas to two arms. Arm A (n = 25) received one intratumoral injection of Delta-24-RGD into biopsy-proven recurrent glioma. The biological endpoint cohort, arm B (n = 12), had an initial intratumoral injection via an implanted catheter and then 14 days later via en bloc tumor/catheter resection, which was done to obtain posttreatment specimens. There was then a subsequent injection in arm B of Delta-24-RGD into the postresection cavity.

One requirement of the study&rsquo;s eligibility criteria was that each patient&rsquo;s glioma type was limited to glioblastoma, gliosarcoma, anaplastic gliomas, anaplastic infiltrating glioma, mixed anaplastic glioma, and anaplastic ependymoma. All patients had to have unequivocal evidence of tumor recurrence or progression via MRI within 15 days before the baseline procedure. Patients had to have failed prior surgical resection, biopsy, chemotherapy, or radiation. Physician investigators had to agree that the injection would not deliver Delta-24-RGD into the ventricular system. Additionally, patients may or may not have had previous chemotherapy.

Researchers escalated the dose in eight cohorts. The maximum tolerated dose was 3 x 10

Median overall survival was 11 months. Three patients (12%) had complete responses, which Lang said was a particularly noteworthy result. These patients are still alive and have no evidence of disease 3.2, 2, and 1.75 years after treatment. A review of serial MRIs showed increased enhancement before tumor regression, which was consistent with inflammatory-mediated responses. These three responders had 10- to 1000-fold increases in interleukin 12p70, the latter of which induces Th1 responses and cell-mediated immunity.

In a symptomatic patient in group A, histological analysis of a resected tumor identified macrophages and CD8 inflammatory-mediated responses during the period of increased MRI enhancement.

As noted, the biological specimens showed that the virus is capable of infecting, replicating in, and killing glioma cells in patients, the researchers concluded. &ldquo;Viral-induced and anti-tumor immunity likely plays a role in the antiglioma effect,&rdquo; said Lang, noting that researchers came to this conclusion based on imaging and correlative histological and cytokine studies.

Delta-24-RGD had a &ldquo;favorable toxicity profile,&rdquo; according to Lang et al.

Future research will include what may be unique about the immune system of the three patients who responded to the virus, Lang said. Researchers also want to see what can be applied to others based on the findings from those responders. &ldquo;Can we make patients who didn&rsquo;t respond look like the 12% who did in some way? This is a great area of research we need to work on,&rdquo; he said.

Lang FF, Conrad C, Gomez-Manzano C, et al. Phase I clinical trial of oncolytic virus Delta-24-RGD (DNX-2401) with biological endpoints: implications for viro-immunotherapy. Presented at: 19th Annual Meeting of the Society for Neuro-Oncology; November 13-16, 2014; Miami, FL. Abstract NT-18.

According to data from a phase I study, the oncolytic virus Delta-24-RGD can infect, replicate, and kill glioma cells in patients.

Oncolytic Virus Shows Promise in Phase I Glioma Study

Adjuvant temozolomide and the use of the Novo Tumor Treating Fields (NovoTTF) system led to longer progression-free survival and overall survival in patients with glioblastoma, according to late-breaking results from a phase III trial presented at the Society for Neuro-Oncology (SNO) Annual Meeting.

&ldquo;A new cancer treatment modality has been born,&rdquo; said Roger Stupp, MD, the trial&rsquo;s principal investigator, reporting the data from the EF-14 study, a prospective, multicenter, international trial of NovoTTF-100A in combination with temozolomide conducted across 83 sites in 12 countries.  Stupp is a professor and chairman of the Department of Oncology, and director, University Hospital Cancer Center, at the University of Zurich in Switzerland.

NovoTTF, manufactured by Novocure, is a portable, noninvasive, battery-operated device which attaches to the patient&rsquo;s head to deliver tumor treating fields to the brain. The NovoTTF appears to slow and reverse tumor growth by inhibiting mitosis. &ldquo;It was shown in preclinical data that the device could inhibit tumor growth,&rdquo; Stupp explained.

Patients use the system at home and may wear it as long as 20 to 22 hours a day. As manufacturers refine the device, it continues to get smaller, Stupp added. The NovoTTF-100A system is approved by the FDA to treat adults 22 and older with GBM that recurs or progresses after receiving chemotherapy and radiation therapy.

After receiving radiotherapy with concomitant temozolomide, the study&rsquo;s 315 patients were randomized 2:1 to receive NovoTTF and temozolomide in combination (n = 210) or temozolomide alone (105 patients). The study&rsquo;s primary endpoint was progression-free survival (PFS), and its secondary endpoint was overall survival (OS).

Eligibility criteria included pathologic evidence of glioblastoma using World Health Organization classification criteria, being aged 18 or older, having maximal debulking surgery and radiotherapy along with temozolomide, a Karnofsky performance status of 70% or higher, and a life expectancy of at least 3 months. Patients had to have used a stable or decreasing dose of steroids, and the interval since radiation therapy had to have been more than 29 days but fewer than 49 days.

Patient characteristics were similar in both groups, with an average age of 57 for the combination group and 58 for the temozolomide-only control arm. Tumor resection was 89% and 90%, respectively, and Karnofsky performance status was 90% in both groups. Of the 60% of patients who were assessable for MGMT promoter methylation status, 39% and 41% were methylated, respectively.

Median PFS was 7.1 months with the combination and 4 months in the temozolomide-only group (HR = 0.63;

= .001). OS was 19.6 months and 16.6 months, respectively (HR = 0.75;

= .034), and the 2-year survival rate was 43% and 29%, respectively.

&ldquo;If you are a patient, [those numbers] are meaningful. If you are an investigator, you want more. However, it&rsquo;s a step forward,&rdquo; Stupp said. The results led to early termination of the trial, and all patients in the control arm were allowed to receive the combination.

Skin irritation occurred in 45% of patients. Severe seizures occurred at a frequency of 7% in both groups.

The data reported at the SNO meeting were after a minimum 18-month follow-up. Researchers had compiled and analyzed the data 4 weeks before the meeting, Stupp noted. Future research will evaluate quality of life and survival at 1 and 2 years.

Although researchers wondered if patients would feel anxious about using the device, Stupp said in his own clinical experience, patients actually feel motivated by it. &ldquo;They feel like they&rsquo;re doing something [to help themselves],&rdquo; he said. &ldquo;That was striking to me.&rdquo;

Stupp R, Wong E, Scott C, et al. Interim analysis of the EF-14 trial: a prospective, multicenter trial of NovoTTF-100A together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM. Presented at: 19th Annual Meeting of the Society for Neuro-Oncology; November 13-16, 2014: Miami, FL.

Adjuvant temozolomide and the use of the Novo Tumor Treating Fields (NovoTTF) system led to longer progression-free survival and overall survival in patients with glioblastoma.

NovoTTF and Temozolomide Extend OS, PFS in Glioblastoma

The vaccine rindopepimut appears to benefit patients with

epidermal growth factor receptor variant III mutation

) in glioblastoma with regard to progression-free survival (PFS) and overall survival (OS). This group of patients has traditionally poor outcomes.

Evangelia Razis, MD, PhD, Hygeia Hospital, Athens, Greece, spoke of the compassionate use of rindopepimut in combination with other anticancer treatments at the Society for Neuro-Oncology&rsquo;s (SNO) annual meeting in Miami Beach, Fla, on November 14, 2014.

Rindopepimut has a unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH). It is delivered intradermally with granulocyte macrophage colony-stimulating factor. The vaccine generates a specific immune response against

-expressing glioblastoma, according to Razis.

The compassionate use study includes patients who did not qualify for enrollment in an open-label trial of the vaccine, she explained.

&ldquo;We&rsquo;re now presenting data from 64 patients treated at 23 sites in 6 countries,&rdquo; she said.

Patients included in the study had recently diagnosed and histologically confirmed glioblastoma, confirmed

mutation, previous or planned standard conformal radiation therapy with temozolomide, systemic corticosteroid use of 2 mg or less daily, and no autoimmune disease or concurrent conditions that would affect a patient&rsquo;s ability to benefit from dosing.

Most patients received a monthly dose of rindopepimut after receiving an initial dose for 2-week periods.

Razis reported on data from 42 patients, 12 who had newly diagnosed glioblastoma that was resected or inoperable, and 30 with recurrent disease.

The median patient age was 53 years (15-70 years), and the median time from diagnosis was 14.5 months.

) methylation was present in 9/17; all patients tested were negative for isocitrate dehydrogenase-1 (IDH1) and IDH2.

Researchers found that rindopepimut was well tolerated when given in combination with temozolomide (57%), bevacizumab (57%), and other agents (17%). Treatment duration was a median of 3.7 months.

Many patients had mild reactions at the site of injection; one patient had serious cerebral edema that was thought to be treatment related, and another patient had a grade 1 headache. No patients had to discontinue therapy, although one patient decided to stop. Fourteen patients still use rindopepimut, according to Razis.

The median peak rindopepimut-induced anti-

titer was 1:1,200, according to the study abstract.

Tumor responseindicated by more than 50% shrinkage&mdash;was seen by researchers in 9 patients who had received the vaccine along with other agents. Three of the 9 patients had newly diagnosed glioblastoma, and 6 patients had recurrent disease. Eight of the 9 patients received recurrent temozolomide, and 4 patients received bevacizumab.

There was one patient who had complete response (CR) during treatment with several agents, including rindopepimut, erlotinib, temozolomide, and bevacizumab. This same patient has continued rindopepimut for more than 5 years with no recurrence of disease.

Another patient who received rindopepimut and temozolomide for approximately 9 months was shown on biopsy to have eliminated

The median PFS was 9.1 and 2.5 months in in patients with newly diagnosed and recurrent glioblastoma, respectively.

&ldquo;Six patients had PFS for more than a year on treatment,&rdquo; Razis said. Three of those patients had newly diagnosed disease, while the other 3 had recurrent disease. Overall survival was 15.7 and 8.7 months from the first vaccination, respectively.

Rindopepimut is undergoing further investigation. &ldquo;The efficacy of rindopepimut is being studied in the ACT-IV trial,&rdquo; as well as in the phase II ReACT clinical study, data from which was presented earlier in the SNO meeting by David Reardon, MD, from Dana-Farber Cancer Institute, Boston, Massachusetts. Researchers from ReACT found a 27% PFS at 6 months for patients receiving both the vaccine and bevacizumab compared with 11% for those receiving the control and bevacizumab.

Future research should also pair rindopepimut with bevacizumab, additional tumor antigens, and selected chemotherapy radiation, according to Razis.

&ldquo;Rindopepimut in combination with various anticancer therapies resulted in robust anti-

humoral response with minimal toxicity,&rdquo; she concluded.

Razis E, Vlahovic G, Recht L, et al. Vaccination against epidermal growth factor receptor variant III in glioblastoma: the rindopepimut compassionate use experience. Presented at the Society for Neuro-Oncology&rsquo;s Annual Meeting. Miami Beach, Florida. November 14, 2014. Abstract IT-28

The vaccine rindopepimut appears to benefit patients with epidermal growth factor receptor variant III mutation (EGFRvIII) in glioblastoma with regard to  progression-free survival (PFS) and overall survival (OS).

Vanessa Caceres | Authors

Articles

Immunotherapyâ€™s Potential in Neuro-Oncology

Oncolytic Virus Shows Promise in Phase I Glioma Study

NovoTTF and Temozolomide Extend OS, PFS in Glioblastoma

Rindopepimut Benefits Patients With EGFRvIII Mutation in Glioblastoma