Rethinking Immunotherapy for Brain Tumors

As highlighted in our prior articles, growing evidence indicates that the field of cancer immunotherapy, broadly defined as including passive immunization, active immunization, and immunostimulation, is coming of age.? More than 40 unique active cancer immunotherapies are currently being tested in over 60 clinical trials, with nearly a dozen readouts from randomized Phase 2 or Phase 3 trials expected during the next 12-months.

Immunotherapy for cancers of the central nervous system [CNS], however, continues to be met with skepticism. ?Amongst the reasons for such incredulity are concerns that the nervous system may be immunologically privileged[i] and the presence of the blood-brain barrier, which only allows entry of select immune cells from the peripheral blood into the brain. ?However, all of these premises have now been substantially discounted and tumors in the CNS should not be considered ?off-limits? to immunotherapy[ii].

In addition, recent observations of how the CNS system behaves and interacts with the immune system have shed some light into the potential role of immunotherapy in the treatment of brain cancer. ?Consider the following facts:

• People with impaired immune systems have an increased risk of developing CNS lymphomas[iii], suggesting that the immune system has a role in the manifestation of tumors in these patients. ?People with compromised immune systems include organ transplantation patients taking immunosuppressive drugs, HIV patients, and cancer patients being treated with chemotherapy, which can weaken immune functionality.
• Bridget McCarthy, Ph.D. of the University of Illinois at Chicago found that patients with gliomas were significantly less likely to report having any type of allergy. ?In fact, patients who had more types of allergies, such as seasonal, medication, pet, or food allergies, had up to a 64% reduction in risk of developing glioma[iv]. This suggests a relationship between immunological activity and potential protection from the development of CNS tumors.
• Neurologists and neurosurgeons provide anecdotal reports that glioma patients who experience postoperative infections near the tumor bed seem to do better than the average patient similar to the observations made over a century ago by Coley[v]. ?This suggests that exogenous factors, such as infections, may result in the activation of the immune system and improve the odds of combating CNS tumors.

Collectively, these observations suggest that proper activation of the immune system in patients with CNS tumors could be beneficial.? Accordingly, we sought to review select companies advancing immunotherapy approaches for brain tumors [see Table 1].

Table 1. Eight Companies with Immunotherapy Approaches for Brain Tumors

Company	Market Cap	Clinical Pipeline	Corporate Partner(s)	Stage(s) [# of programs]
Agenus, Inc. (AGEN)	$62M	Prophage Series*, QS-21 Stimulon? adjuvant, HerpV	GlaxoSmithKline (GSK), Johnson & Johnson (JNJ), ChemRar, and Integrated Biotherapeutics	Phase III [4], Phase II [10], Phase 1 [1]
Celldex Therapeutics (CLDX)	$202M	Rindopepimut [CDX-110]; CDX-011, CDX-1401, CDX-1127, CDX-301	n/a	Phase III [1], Phase II [3], Phase I [2]
Immatics Biotechnologies (private)	n/a	IMA-901, IMA-910, IMA-950	n/a	Phase III [1], Phase II [1], Phase I [1]
ImmunoCellular Therapeutics (IMUC)	$72M	ICT-107	n/a	Phase II [1]
Innocell Corp (031390.KQ)	n/a	Immuncell-LC**	n/a	Phase III [1]
Northwest Biotherapeutics (NWBO)	$31M	DCVax?	n/a	Phase II [1]
Oncovir, Inc. (private)	n/a	Hiltonol (Poly-ICLC)	n/a	Phase II [2], Phase I [2]
TVAX Biomedical (private, IPO planned)	~$80M at IPO	TV1-Brain-1, TV1-Kidney-1	n/a	Phase II [1]

* Marketed in Russia as Oncophage? for intermediate-risk renal cell carcinoma,?** Marketed in Korea for hepatocellular carcinoma

About Glioma

Glioma is the most common form of primary brain tumors. ?They are solid tumors that arise from glial cells, which help support the function of the neurons.? Glial cells include astrocytes, oligodendrocytes and ependymal cells.? The overgrowth of abnormal glial cells may begin in the brain or spinal cord tissues.

Gliomas can be divided into two categories: low-grade, which are not benign but have a better prognosis, or high-grade, which are malignant and often cause death within months, despite surgery or treatment with chemotherapy or radiation, according to the National Cancer Institute.

Glioblastoma multiforme [GBM], a high-grade glioma, is the most common and aggressive primary brain tumor.? In contrast, tumors originating from astrocytes [astrocytoma] range from Grade 1, which are very benign, to Grade 4, which is the same as a glioblastoma.

Amenable to Immunotherapy

Beyond recent observations suggesting a role for immunotherapy in treating brain tumors, several other factors make glioma an ideal indication for immunotherapy.? First, glioma rarely metastasizes beyond the brain, resulting in a low overall tumor burden within the body.? Second, while the blood-brain barrier is thought to restrict entry of immune cells from the peripheral blood into the brain of healthy individuals, glioma disrupts the blood brain barrier, allowing for the freer trafficking of T-cells.? Finally, glioma tumor tissue, especially in patients who are newly diagnosed, is amenable to surgical resection therefore lowering tumor burden at time of vaccination [minimal residual disease].? Studying cancer immunotherapy in settings with bulky or metastatic disease might help explain some of the past failures, as the immune system may not be able to thwart such extensive disease.? Accordingly, minimal disease settings are ideal for cancer immunotherapy.

Strategies for Immunotherapy in Glioma

In general, two categories of immunotherapeutic approaches for the treatment of glioma are currently being pursued: cell-free vaccines and cell-based vaccines.

Cell-free vaccines

Cell-free vaccines may contain heat-shock protein-peptide (HSP) complexes derived from the patient?s tumor following surgery [autologous] or incorporate one or more defined tumor peptides plus an adjuvant [non-autologous].? The following companies are advancing cell-free vaccines:

• Agenus, Inc.: autologous HSPs that elicit both CD4+ and CD8+ T-cell response and also innate response
• Celldex Therapeutics: a single EGFRvIII peptide
• Immatics Biotechnologies: 11 tumor associated, synthetic peptides

Cell-based vaccines

Cell-based vaccines often incorporate dendritic cells [DC] pulsed with defined tumor peptides, tumor cell lysate, brain tumor stem cell mRNA.? Alternatively, some cell-based vaccines consist of adoptive lymphocyte infusion and/or irradiated tumor cells.? The following companies are advancing cell-based vaccines:

• ImmunoCellular Therapeutics: DCs pulsed with shared HLA-A1/A2 tumor peptides
• Innocell Corp: adaptive transfer of cytokine-induced T-cells/NK cells
• Northwest Biotherapeutics: DCs pulsed with tumor lysate
• Oncovir, Inc.: a-type 1 polarized DCs pulsed with defined HLA-A2 peptides plus poly-ICLC adjuvant
• TVAX Biomedical: whole cell vaccination plus adoptive transfer of lymphocytes

To date, commercializing cell-based vaccines has been challenging.? For example, Dendreon?s (DNDN) Provenge? [sipuleucel-T] for prostate cancer is a cell-based vaccine that fell short of Wall Street analyst expectations during the first full year of commercial launch.? Provenge and other DC-based cancer vaccines require leukopherisis to acquire a patient?s dendritic cells. ?This process adds to the overall cost of producing the vaccine and makes the logistics somewhat complicated. ?In contrast, cell-free vaccines can be derived from synthetic peptides or from the patient?s tumor following standard surgical resection, making the treatment process more user friendly from both a physician and patient perspective.

Clinical Development of Immunotherapy for GBM

The current standard of care for GBM, based on a prospective, randomized controlled trial published in 2005, involves maximal surgical resection with adjuvant radiation therapy and temozolomide[vi].? Despite this therapeutic regimen, median overall survival is between 14.6 and 19.6 months for newly diagnosed patients and between 6 and 9 months for recurrent GBM[vii]^,[viii].

While immunotherapy approaches for GBM would be expected to perform better in the newly diagnosed setting, some companies first established proof-of-concept for their product candidates in the relapsed setting.? Due to the shorter expected survival, these Phase I/II studies may be faster and less expensive.? If hints of efficacy are observed in the relapsed disease setting, the product candidates can then be explored in the newly diagnosed setting.

In view of differences among histologies, ages, trial designs, and the small number of patients with immunotherapy studies published to date in the recurrent GBM setting, comparing and contrasting the findings is difficult [see Table 2].? For example, in the largest single study [56 patients] from the Catholic University of Leuven, the median age was the lowest [45 years] due to the inclusion of children above the age of seven.? In addition, some of the studies included patients that were not diagnosed with GBM, such as astrocytomas that can vary in grade.

In contrast to the results obtained with current standard of care, several of the studies with cancer vaccines for recurrent GBM have demonstrated a median overall survival greater than nine months. ?Some of these trials where immune responses have been measured, such as the Prophage G-200 [HSPPC-96] trial, have shown impressive immunological activity post vaccination. ?More impressive and certainly more relevant, these responses have also been measurable locally at the tumor site, which suggests such a response may be more meaningful from the perspective of effectively combating the disease.

Table 2. Recurrent GBM Vaccine Data

Company/ Institution	Product/ Reference	Clinical Stage	# Patients w/ GBM	Median Age	Overall Survival
Agenus, Inc.	Prophage G-200 [HSPPC-96][ix]	Phase II	33/33	53 [n=33]	11 [n=33]
Catholic University of Leuven, Belgium	DC pulsed w/ tumor lysate [+/- booster of lysate without DC][x]	Phase I/II	56/56	45 [n=56]	9.6 [n=56]
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, California	DC pulsed w/ tumor lysate[xi]	Phase II	21/32	54 [n=32]	13.4 [n=12] to 20 [n=9]
TVAX Biomedical	TV1-Brain-1[xii]	Phase I	16/19	50 [n=19]	12 [n=19]
Niigata University School of Medicine, Niigata, Japan	DC pulsed w/ tumor lysate[xiii]	Phase I/II	18/24	53 [n=18]	16 [n=18]
Oncovir/University of Pittsburgh	a-type 1 polarized DCs pulsed w/ defined HLA-A2 peptides plus poly-ICLC adjuvant[xiv]	Phase I/II	13/22	54 [n=13]	12 [n=13]

?

Several companies are also currently conducting immunotherapy trials in newly diagnosed GBM, with encouraging results presented to date, including Agenus [ClinicalTrials.gov: NCT00905060], Celldex Therapeutics [ClinicalTrials.gov: NCT01480479], Immatics [ClinicalTrials.gov: NCT01222221], ImmunoCellular [ClinicalTrials.gov: NCT01280552], Innocell Corporation [ClinicalTrials.gov: NCT00807027], and Northwest Biotherapeutics [ClinicalTrials.gov: NCT00045968].

An important future direction for the successful treatment of these very difficult tumors may involve the combination of immunotherapeutic agents with other synergistic treatments. ?Such approaches could simultaneously address the immunosuppressive, angiogenic, invasive, and hypoxic nature of GBM.? In this regard, combination approaches with Avastin? [bevacizumab] and other potentially synergistic agents would make imminent sense to pursue.

Note: For further information on this topic, click here to view a replay of the plenary session ?Advances in immunotherapy for glioma? by Andrew T. Parsa, M.D., Ph.D., University of California, San Francisco, from MD Becker Partners? 2nd Annual ?Cancer Immunotherapy: A Long-Awaited Reality? Conference held October 6, 2011.

References

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[ii] Heimberger AB, Sampson JH.? Immunotherapy coming of age: What will it take to make it standard of care for glioblastoma?? Neuro Oncol. 2011 Jan;13(1):3-13. Epub 2010 Dec 10.

[iii] Guinto G, F?lix I, Ar?chiga N, Arteaga V, Kovacs K. Primary central nervous system lymphomas in immunocompetent patients.? Histol Histopathol. 2004 Jul;19(3):963-72.

[iv] McCarthy BJ, Rankin K, Il?yasova D, Erdal S, Vick N, Ali-Osman F, Bigner DD, Davis F. Assessment of type of allergy and antihistamine use in the development of glioma.? Cancer Epidemiol Biomarkers Prev. 2011 Feb;20(2):370-8.

[v] Nauts HC, McLaren JR. Coley toxins ? the first century.? Adv Exp Med Biol. 1990;267:483-500.

[vi] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.? N Engl J Med. 2005 Mar 10;352(10):987-96.

[vii] Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J; NABTT CNS Consortium.? Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States.? Clin Cancer Res. 2010 Apr 15;16(8):2443-9. Epub 2010 Apr 6.

[viii] Caroli M, Locatelli M, Campanella R, Motta F, Mora A, Prada F, Borsa S, Martinelli-Boneschi F, Saladino A, Gaini SM.? Temozolomide in glioblastoma: results of administration at first relapse and in newly diagnosed cases. Is still proposable an alternative schedule to concomitant protocol?? J Neurooncol. 2007 Aug;84(1):71-7. Epub 2007 Mar 15.

[ix] A. Parsa, C. Crane, S. Han, V. Kivett, A. Fedoroff, N. A. Butowski, S. M. Chang, J. L. Clarke, M. S. Berger, M. McDermott, M. Aghi, C. Yanes, M. Prados, A. E. Sloan, J. N. Bruce.? Autologous heat shock protein vaccine (HSPPC-96) for patients with recurrent glioblastoma (GBM): Results of a phase II multicenter clinical trial with immunological assessments.? J Clin Oncol 29: 2011 (suppl; abstr 2565)

[x] De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE, Wagner S, Kaempgen E, Van Gool SW.? Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme.? Clin Cancer Res. 2008 May 15;14(10):3098-104.

[xi] Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, Goldfinger D, Ng H, Irvin D, Yu JS.? Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.? Cancer Res. 2008 Jul 15;68(14):5955-64.

[xii] Sloan AE, Dansey R, Zamorano L, Barger G, Hamm C, Diaz F, Baynes R, Wood G.? Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes.? Neurosurg Focus. 2000 Dec 15;9(6):e9.

[xiii] Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, Yoshida S, Abe T, Narita M, Takahashi M, Tanaka R.? Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial.? Clin Cancer Res. 2005 Jun 1;11(11):4160-7.

[xiv] Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, Mintz AH, Engh JA, Bartlett DL, Brown CK, Zeh H, Holtzman MP, Reinhart TA, Whiteside TL, Butterfield LH, Hamilton RL, Potter DM, Pollack IF, Salazar AM, Lieberman FS.? Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma.? J Clin Oncol. 2011 Jan 20;29(3):330-6. Epub 2010 Dec 13.

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