Mechanism of Pathway: Phosphatidylserine, an Immune-Modulating Checkpoint, Ushers in the Next Wave of Immuno-Oncology Targets
Phosphatidylserine, an Immune-Modulating Checkpoint, Ushers in the Next Wave of Immuno-Oncology Targets
The immune system recognizes and is poised to eliminate cancer but is held in check by a plethora of inhibitory pathways that regulate cellular immune responses.1 These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during antimicrobial immune responses, can be co-opted by cancer to evade immune destruction.2-5 The inhibition of these immune checkpoints has led to important clinical advances and provided new weapons against cancer.6,7 While targeting immune checkpoints, such as programmed death-1 (PD-1), PD-1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), has resulted in durable, long-lasting responses in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumor response, this benefit is seen in only a fraction of patients.5-7 The underlying cause for the failure of immune checkpoint blockade is an overwhelming, persistent, and multifocal immune suppression in the tumor microenvironment.8 Therefore, as the field of immune-oncology moves forward, it is becoming clear that additional, “next-generation” immune checkpoints, such as phosphatidylserine (PS), an immune checkpoint distinct from PD-1/PD-L1 and CTLA-4, must be targeted, and strategies for combination therapies acting on diverse pathways should be assessed for the potential to provide survival benefits for greater numbers of patients.7,9
PS: an Upstream Immune-Modulating Checkpoint
In a healthy body, the immune system functions as a powerful defense against foreign invaders and host cells that are undergoing malignant transformation. However, the rise of malignancy suggests that the dynamics of the immune system have been compromised and suppressed, allowing cancer cells to evade immunological destruction.10
PS is a highly immunosuppressive phospholipid molecule that is actively maintained on the inner leaflet of the plasma membrane of healthy cells. As a cell dies a natural death, PS “flips” and becomes exposed on the outer surface of the membrane. When PS is exposed on the outside of the membrane, it engages PS receptors on immune cells and signals them not to mount an attack on the dying cells’ living counterparts.11 This allows the body’s phagocytic cells to gently remove the dying cells without prompting an inflammatory response that would lead to autoimmunity.12,13 PS is also flipped to the outer leaflet of the plasma membrane in cells that have undergone stress, such as hypoxia/reoxygenation, oxidative stress, and exposure to certain cytokines.
PS exposure can be subverted by cancer cells as a ploy to escape host defenses: tumors compromise the body’s normal immunosuppressive process of clearance/disposal of dying cells through PS-signaling mechanisms to evade immune detection.14 By exploiting this fundamental upstream immune checkpoint, cancer cells avoid immune activation and initiate tumor growth progresses. High levels of PS are exposed on cells in the tumor environment and on small particles (known as exosomes) that are shed from tumor cells.14,15 Exposed PS is engaged as a ligand or coligand by PS receptors on immune cells, leading to the secretion of immunosuppressive cytokines, including transforming growth factor beta (TGF-β) and interleukin (IL)-10, as well as angiogenic factors such as vascular endothelial growth factor, from tumor-promoting myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages, which fail to differentiate into M1-like tumor-killing macrophages and natural killer cells. Furthermore, the immunosuppressive microenvironment driven by exposed PS inhibits dendritic cell maturation, reducing the development of tumor-specific cytotoxic T-cell responses. Thus, PS exposure suppresses both innate and adaptive antitumor immune responses.
The exposure of PS in the tumor microenvironment is increased significantly in response to chemotherapy and radiation therapy, leading to increased immunosuppression and angiogenesis.15-18 Therefore, PS is a promising target for anticancer therapy that has particular potential for use in combination with chemotherapy, radiation, and other therapies that drive the further expression of PS.
Bavituximab: a Novel, Investigational Immunotherapy Agent Targeting PS in the Vasculature of the Tumor Microenvironment
Bavituximab, a unique immunotherapy with a novel mechanism of action, is a first-in-class investigational monoclonal antibody that targets PS.19 PS-targeting agents block PS-mediated immunosuppression by multifocal reprogramming of immune cells in the tumor microenvironment to support immune activation.8 Preclinical data demonstrate that bavituximab blocks PS immunosuppressive signaling, provides specificity for innate immune responses, and activates T-cell–driven adaptive immunopathways to stimulate an effective immune response to the tumor.20 After binding exposed PS in tumors, bavituximab engages Fc-γ receptors on MDSCs, M2 macrophages, and immature dendritic cells, leading to multiple immunostimulatory changes in the tumor environment.20 These changes include an increase in immunostimulatory cytokines (including tumor necrosis factor alpha [TNF-α] and IL-12), macrophage polarization from an M2 state to a tumor-fighting M1 state, and differentiation of tumor-promoting MDSCs into M1 macrophages and mature dendritic cells.20 Thus, antibody-mediated PS blockade reduces the levels of MDSCs, TGF-β, and IL-10 and increases the levels of TNF-α and IL-12.8 M1 macrophages contribute to tumor destruction through antibody-dependent cellular cytotoxicity, while mature dendritic cells educate T cells, inducing tumor-specific cytotoxic T-cell responses.20,21
Bavituximab potentially combines well with other compounds currently being developed for oncology. Preclinical and early clinical data suggest that combining bavituximab with other treatments, including chemotherapy,17 radiation,21,22 androgen deprivation therapy,23 or other checkpoint inhibitors,24-28 increases therapeutic effectiveness without increasing toxicities.
Bavituximab is currently being evaluated in clinical studies in several solid tumor indications (Table 1), including non–small cell lung cancer (NSCLC), rectal cancer, and advanced melanoma—with additional clinical trials in planning stages. Bavituximab has been granted Fast Track designation by the FDA for the potential second-line treatment of NSCLC.
According to the American Cancer Society, lung cancer is the second most commonly diagnosed cancer in the United States.29 An estimated 221,200 new cases of lung cancer are expected in 2015, accounting for about 13% of all cancer diagnoses. Lung cancer accounts for more deaths than any other cancer in men and women. An estimated 158,040 deaths are expected to occur in 2015, accounting for approximately 27% of all cancer deaths. NSCLC is the most common type of lung cancer, accounting for approximately 83% of lung cancer cases; of these, 25% to 30% are squamous NSCLC, while the rest are nonsquamous.29 When NSCLC is diagnosed in advanced stages, the 5-year survival rates are bleak, with 14% for stage IIIa, 5% for stage IIIb, and 1% for stage IV.30
Docetaxel chemotherapy was approved by the FDA as monotherapy for patients with NSCLC previously treated with a platinum-based chemotherapy based on the results from 2 randomized, controlled studies. In the first study, patients receiving docetaxel had a median survival of 7.5 months, compared with 4.6 months for the control group that received best supportive care. In the second study, patients receiving docetaxel had a median survival of 5.7 months, compared with 5.6 months for the control group.31
Rationale for Combining Bavituximab With Docetaxel
Results from a number of preclinical studies suggest that bavituximab and docetaxel have highly compatible mechanisms of action that support their use in combination. For example, docetaxel has been shown to increase PS exposure,32,33 while bavituximab has been shown to block PS and engage Fc-γ receptors.20 Compelling preclinical data in tumor models have shown a 93% reduction in tumor growth when a bavituximab equivalent was combined with docetaxel; the combination therapy reduced the tumor vessel density and plasma volume in tumors to a greater extent than did the individual drugs, while the combination therapy was no more toxic to the mice than was docetaxel alone.17
Bavituximab as Second-Line Treatment for NSCLC
In light of these results, a phase 2, randomized, double-blind, placebo-controlled study was conducted to evaluate docetaxel with bavituximab or placebo and enrolled 121 patients with previously treated locally advanced or metastatic stage IIIb or IV nonsquamous NSCLC.34 Patients were randomized to receive 1 of 3 treatments: docetaxel plus 3 mg/kg bavituximab, docetaxel plus 1 mg/kg bavituximab, or docetaxel plus placebo. Patients enrolled in the trial were not selected based on genetic or other biomarkers. All patients had confirmed stage IIIb or IV nonsquamous NSCLC and had progressed following 1 prior chemotherapy regimen. The study was designed to evaluate overall response rate (ORR) measured in accordance with Response Evaluation Criteria In Solid Tumors (RECIST), progression-free survival (PFS), duration of response, overall survival (OS), and safety. After study unblinding, vial coding discrepancies were discovered in the placebo and 1 mg/kg vials. As a result, data from these 2 groups were combined for data analysis.
Final results from the study, presented at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO), showed an improvement in median OS of 11.7 months in the 3 mg/kg bavituximab plus docetaxel arm compared with 7.3 months in the combined control arm (docetaxel plus 1 mg/kg bavituximab or placebo) with a persistent separation in the Kaplan-Meier survival curves (hazard ratio, 0.662) (Table 2, Figure). Results also showed that ORR and PFS both favored the 3 mg/kg bavituximab plus docetaxel arm (Table 2). Specifically, data showed an ORR of 17.1% in the 3 mg/kg bavituximab plus docetaxel arm versus 11.3% in the combined control arm and a PFS of 4.2 months in the 3 mg/kg bavituximab plus docetaxel arm versus 3.9 months in the combined control arm. In addition, subgroup analyses of OS by key patient characteristics favored the bavituximab 3 mg/kg arm, including age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, ethnicity, histology, and prior treatment. The results also indicated that the 3 mg/kg bavituximab plus docetaxel combination was well tolerated with no significant differences in adverse events (AEs) between the study groups.
Based on the promising results from the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled study (SUNRISE) is under way comparing bavituximab plus docetaxel versus placebo plus docetaxel as second-line treatment for patients with NSCLC. Patients with stage IIIb/IV nonsquamous NSCLC who have progressed after standard frontline treatment are eligible for enrollment. Patients will be randomized into 1 of 2 treatment arms. All patients will receive up to 6 21-day cycles of docetaxel (75 mg/m2) plus weekly infusions of either bavituximab (3 mg/kg) or placebo, until progression or toxicity. The primary end point of the study will be OS. This study will enroll approximately 600 patients from more than 100 medical centers worldwide.
Bavituximab as Frontline Treatment for NSCLC
Standard-of-care frontline conventional chemotherapy treatment for advanced NSCLC usually involves 2 agents, such as carboplatin and pemetrexed or carboplatin and paclitaxel.35
A phase 1b, open-label, single-arm, multicenter study (NCT01323062) of the combination of carboplatin, pemetrexed, and bavituximab was conducted in 26 patients with previously untreated, locally advanced or metastatic (stage IIIB or IV), nonsquamous NSCLC.36 Results from 23 evaluable patients showed an ORR of 35% (95% CI, 16.4%-57.3%) as measured by RECIST. In addition, data showed a median PFS of 4.8 months (95% CI, 4.0-8.0 months) and a median OS of 12.2 months (95% CI, 8.0-not estimable months). Most AEs observed were consistent with the known safety profile of the chemotherapy agents, with no dose-limiting toxicities or unexpected AEs occurring. All patients experienced at least 1 AE. The most common treatment-related AEs were thrombocytopenia, anemia, neutropenia, fatigue, and nausea, with most AEs being grade ≤2.
A phase 2 open-label study (NCT00687817) of bavituximab plus paclitaxel and carboplatin was conducted in 49 patients with stage IIIB/IV NSCLC.37 The primary efficacy end point of ORR was 40.8% (complete response [CR] 2.0%, partial response [PR] 38.8%). Median PFS and OS were 6.0 and 12.4 months, respectively. Treatment-related AEs occurred in 40.8% of patients. The most common treatment-related AEs were anemia (10.2%), asthenia, vomiting, paresthesia, anorexia, and fatigue (6.1% each). One patient with a central, cavitating, squamous tumor developed fatal hemoptysis and aspiration.
Bavituximab in HER2-Negative Metastatic Breast Cancer
The prognosis for patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer has improved significantly with the emergence of trastuzumab and other anti-HER2 agents, but the great majority of patients with advanced breast cancer have HER2-negative disease, and thus they are not candidates for HER2-targeted therapies.38 ASCO guidelines recommend that different chemotherapy agents should normally be given sequentially (as single agents rather than in combination) to reduce side effects and preserve quality of life.38 Because of the need for more effective therapies for HER2-negative breast cancer, bavituximab is being studied in combination with single-agent chemotherapy.
A phase 1 single-arm, open-label study (NCT01288261) of bavituximab combined with paclitaxel was conducted in patients with HER2-negative metastatic breast cancer.39 Fourteen patients were enrolled; all were evaluable for toxicity, and 13 were evaluable for response. Treatment resulted in an ORR of 85% (11/13 patients) as measured by RECIST, including 2 patients (15%) achieving a CR. Duration of responses ranged from 1.5 to 13 months. Median PFS was 7.3 months (range, 2.8-10.8 months). All 14 patients had at least 1 AE. The majority of the AEs was grade 1 or 2 and attributed to paclitaxel treatment. Grades 1-3 infusion-related reactions were the most common AEs related to bavituximab therapy, resulting in study discontinuation in 2 patients.
Based on these promising results, a phase 2/3 study is planned in which patients with metastatic HER2-negative breast cancer will receive chemotherapy (the physician’s choice of paclitaxel or docetaxel) alone or in combination with bavituximab. If the primary end point of ORR in the phase 2 part is reached, the phase 3 part of the trial will be activated, which will have a primary end point of PFS.
Bavituximab in Advanced Liver Cancer
The majority of patients with liver cancer present with late-stage disease. For patients who are diagnosed at regional stages of the disease, the 5-year survival rate is 7%, and for those diagnosed at distant stages, it drops to 2%.40 Few treatment options exist for patients diagnosed at an advanced stage, but sorafenib, a kinase inhibitor, was approved by the FDA in 2007 for patients with inoperable hepatocellular carcinoma.41 The FDA’s approval of sorafenib was based on the results from a randomized placebo-controlled study in which patients who received sorafenib survived a median of 2.8 months longer than those who received placebo.42 Because of these promising results with single-agent sorafenib, a study was conducted with bavituximab in combination with sorafenib.
A phase 1/2 single-institution, single-arm, open-label study (NCT01264705) of bavituximab combined with sorafenib is being conducted in patients with advanced hepatocellular carcinoma. Results from the phase 2 portion of the study, which were presented at ASCO 2015, showed that the combination of bavituximab and sorafenib is associated with a median time to progression (TTP) of 6.7 months, a median disease-specific survival of 8.7 months, a disease control rate of 58% (22 out of 38 patients), and a 4-month PFS of 62%.43 Two patients (5%) achieved a PR according to RECIST. The secondary end point of median OS was 6.2 months. The authors concluded that, when compared with historical controls, bavituximab and sorafenib combination therapy is associated with improved TTP and 4-month PFS in a patient population with more unfavorable disease biology as demonstrated by a high rate of previous treatment and macrovascular invasion.
Bavituximab as Frontline Treatment for Rectal Cancer
5-Fluorouracil (5-FU) has remained a mainstay in treatment regimens for colon and rectal cancers since its introduction more than 40 years ago; however, despite the importance of 5-FU to cancer care, its short half-life, requirement for a central line, and the need for continuous infusions led researchers to design an oral formulation of the drug, capecitabine.44 The standard treatment for locally advanced rectal cancer involves chemotherapy and radiation, known as 5FUCMT, (the chemotherapy drugs 5-fluorouracil/capecitabine and radiation therapy), prior to surgery.
Preclinical evidence in a rat model of glioblastoma has suggested that bavituximab combined with radiation therapy holds promise as a vascular targeting and immune-enhancement strategy.21
Therefore, an ongoing investigator-sponsored phase 1 study (NCT01634685) has been designed to assess bavituximab in combination with capecitabine and radiation therapy in up to 18 patients with ECOG performance status of 0-1 who have advanced (stage II or III) rectal adenocarcinoma. Patients will receive weekly bavituximab for a total of 8 weeks with administration of capecitabine (825 mg/m2) on each of the 28 days of radiation therapy (1.8 Gy/fraction) over 6 weeks, followed by 2 weeks of bavituximab administration by itself. Surgery will follow the last bavituximab administration by 4 to 8 weeks (ie, 6-10 weeks following completion of radiation therapy). The primary end point is to determine the safety, feasibility, and tolerability with a standard platform of capecitabine and radiation therapy. Secondary end points include ORR and histopathologic response.
Seeking Synergy by Combining Checkpoint Inhibitors
Studies have shown that combining checkpoint inhibitors with different mechanisms of action shows promise in advanced melanoma. Nivolumab (a PD-1 checkpoint inhibitor) and ipilimumab (a CTLA-4 checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. Results from a phase 1 study (NCT0102423) of nivolumab combined with ipilimumab in 53 patients with advanced melanoma showed an ORR of 40% for patients receiving the combination therapy.45 In a phase 1 study (NCT01927419), combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high ORR, including CRs, among 142 patients with previously untreated advanced melanoma.46 Among patients with BRAF wild-type tumors, the rate of confirmed ORR was 61% (44/72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4/37) in the group that received ipilimumab and placebo (ipilimumab monotherapy group) (P <.001), with CRs reported in 16 patients (22%) in the combination group and no patients in the ipilimumab monotherapy group. Drug-related grade 3 or 4 AEs were reported in 54% of the patients who received the combination therapy and in 24% of the patients who received ipilimumab monotherapy. Select AEs with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. In a randomized, double-blind, phase 3 study (NCT01844505), nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with previously untreated, unresectable stage III or IV melanoma.47 Results showed that the median PFS was 11.5 months with the combination of nivolumab and ipilimumab compared with 2.9 months with ipilimumab alone and 6.9 months with nivolumab alone. In patients with tumors positive for PD-L1, the median PFS was 14.0 months in the nivolumab plus ipilimumab group and in the nivolumab-alone group, but in patients with PD-L1–negative tumors, PFS was longer with the combination therapy than with nivolumab alone (11.2 months vs 5.3 months). Treatment-related AEs of grade 3 or 4 occurred in 16.3% of the patients treated with nivolumab alone, 27.3% of patients treated with ipilimumab alone, and 55.0% of those who received the combination therapy.
Preclinical Studies Suggest Promise for the Combination of Bavituximab With Either an Anti–PD-1 or an Anti–CTLA-4 Antibody
Preclinical studies have shown synergy of PS-specific antibody treatment with CTLA-4–specific and PD-1–specific antibodies in mouse models through effects on MDSC and lymphocyte activity. In a K1735 mouse melanoma model, the antitumor effect of the combination of a PS-targeting antibody with antibodies that inhibit the downstream immune checkpoints PD-1 or CTLA-4 was examined.48
Tumor-bearing mice were treated with each antibody alone or the combination. Combination therapy potently suppressed tumor growth and improved OS compared with single-agent treatment. Flow cytometry revealed that combination therapy induced the highest ratio of tumor-infiltrating immune effector cells to suppressor cells. Importantly, combination treatment also significantly decreased the levels of MDSCs in the spleen. In addition, inhibition of PS and PD-1 or CTLA-4 resulted in significantly more IL-2– and IFN-γ–secreting splenic CD4+ and CD8+ T cells than any single-agent treatment. Finally, combined immune checkpoint blockade did not induce any observable toxicity following multiple treatment doses. In summary, these findings demonstrate that the combination of antibody-mediated PS blockade with an inhibition of established immune checkpoints (eg, PD-1 and CTLA-4) represents a promising strategy for cancer immunotherapy.
Results presented at ASCO 2015 showed that blocking PS with a PS-targeting antibody enhances the antitumor activity of combination therapies, including anti–PD-1 and anti–CTLA-4 antibodies, in an immune competent model of breast cancer and in preclinical models of melanoma.26 In a breast cancer model, researchers found that the combination of PS blockade and an anti–PD-1 antibody promoted strong and localized antitumor responses without the side effects of systemic immune activation. In models of melanoma, the combination of PS blockade with either an anti–PD-1 or anti–CTLA-4 antibody showed significantly superior tumor growth inhibition over single-agent treatment, with many animals achieving complete tumor regressions. No toxicity was observed in any of the treatment groups following multiple treatment doses. The researchers concluded that these data support the continued investigation of bavituximab as an immunomodulatory treatment in PD-1–sensitive and anti–PD-1–resistant/unresponsive tumors.
ORRs of approximately 20% have been reported in patients with advanced NSCLC treated with antibodies (eg, nivolumab, pembrolizumab) targeting the immune checkpoint, PD-1 on activated T cells, or its primary ligand, PD-L1, expressed within the tumor microenvironment.49 Although PD-1/PD-L1 blockade therapy provides clinical benefits to approximately 20% of patients with advanced NSCLC, about 80% of patients still remain refractory to this treatment. Therefore, new molecules and combinations are urgently needed to address primary and secondary nonresponsiveness to these new agents.
Evidence indicates that blocking PS improves the efficacy of PD-1 and CTLA-4 tumor immunotherapy.8 In a phase 2 clinical study, immunohistochemical evaluation of hepatocellular carcinoma tumor tissues after combination treatment indicated an increase of immune infiltrates and PD-1 expression, raising the potential of a clinically meaningful antitumor immune response.8
At ASCO 2015, initial data were presented from a pilot translational study analyzing tumor tissue from 6 lung cancer patients to evaluate the immunomodulatory effects of bavituximab in a human ex vivo model of NSCLC.25 New data generated from additional assays further validated previously reported results showing that ex vivo drug treatment with bavituximab, alone and in combination with docetaxel, elicits an immune response in tumors from NSCLC patients with negative PD-L1 and low PD-1 expression. Specifically, data showed activation of tumor-infiltrating lymphocytes by polarization of the tumor microenvironment from immunosuppressive to immunostimulatory. Results in this pilot translational study also identified low PD-L1 and PD-1 expression as a potential biomarker of responsiveness to bavituximab treatment, converting low PD-1/PD-L1 axis expression to potential responsiveness to anti–PD-1 therapy in lung cancer.
Upcoming Study of Bavituximab Combined With Nivolumab in NSCLC
Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with its ligands, PD-L1 and PD-L2, thereby releasing PD-1 pathway-
mediated inhibition of the immune response, including antitumor immune response.50 In March 2015, the FDA approved the immunotherapy nivolumab for the treatment of advanced squamous NSCLC that has failed chemotherapy.50 This approval was based on results from a phase 3 study that showed that patients receiving nivolumab had a median OS of 9.2 months compared with 6.0 months in patients receiving docetaxel. This translates into a 41% reduced risk of death.50
A phase 2, open-label, multicenter, randomized study is planned in which bavituximab combined with nivolumab will be compared with nivolumab alone in patients with previously treated NSCLC. Enrollment will include patients with squamous and nonsquamous NSCLC who have not received a prior PD-L1 or PD-1 inhibitor. The primary end point of this study will be ORR; secondary end points will include tumor response and duration, PFS, OS, and safety.
Upcoming Study of Bavituximab Combined With Durvalumab in Solid Tumors
A phase 1/1b study is also planned in which bavituximab and durvalumab (MEDI4736), an investigational anti–PD-L1 immune checkpoint inhibitor, will be combined with chemotherapy in patients with various solid tumors. The phase 1 part of the study is expected to establish a recommended dose regimen for the combination, and the phase 1b part of the study will assess the safety and efficacy of the investigational combination.
PS is an immune checkpoint distinct from PD-1/PD-L1 and CTLA-4. PS is a highly immunosuppressive phospholipid molecule usually located on the interior side of the plasma membrane of healthy cells. As a cell dies a natural death, PS “flips” and becomes exposed on the outer surface of the membrane. When PS is exposed, it engages PS receptors on immune cells and signals them not to attack dying cells. This allows the body’s phagocytic cells to gently remove the dying cells without prompting an inflammatory response.
PS exposure is subverted by cancer cells as a ploy to escape host defenses: tumors compromise the body’s normal immunosuppressive process of clearance/disposal of dying cells through PS-signaling mechanisms to evade immune detection. By exploiting this natural upstream immune checkpoint, cancer can promote tumor growth. High levels of PS are exposed on cells in the tumor environment, as well as on small particles (known as exosomes) that are shed from tumor cells. This exposed PS is engaged by PS receptors on immune cells, leading to the secretion of immunosuppressive cytokines, including TGF-β and IL-10, from tumor-promoting MDSCs and M2-like tumor-associated macrophages. Furthermore, the immunosuppressive microenvironment driven by exposed PS inhibits dendritic cell maturation and prevents the development of tumor-specific cytotoxic T-cell responses.
PS exposure in the tumor microenvironment is immunosuppressive and increases in response to chemotherapy and radiation therapy. PS holds particular promise as a target for anticancer therapy when used in combination with chemotherapy and radiation therapy.
Bavituximab is an investigational monoclonal antibody that inhibits PS signaling. Preclinical data show that bavituximab blocks PS immunosuppressive signaling, provides specificity for innate immune responses, and activates T-cell–driven adaptive immunopathways that reactivate a therapeutically effective immune response to the tumor. Early preclinical and clinical data suggest that combining bavituximab with other treatments, including chemotherapy, androgen deprivation therapy, or other checkpoint inhibitors, increases therapeutic effectiveness without increasing toxicities. Bavituximab is currently being evaluated in clinical studies in several solid tumor indications, including NSCLC, HER2-negative breast cancer, rectal cancer, and advanced melanoma—with additional clinical trials in planning stages.
- Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450-461.
- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.
- Blank CU. The perspective of immunotherapy: new molecules and new mechanisms of action in immune modulation. Curr Opin Oncol. 2014;26:204-214.
- Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.
- Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14:561-584.
- Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205-214.
- Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56-61.
- Yopp A, Kallinteris N, Huang X, et al. Antibody-mediated blockade of phosphatidylserine enhances the antitumor activity of targeted therapy and immune checkpoint inhibitors by affecting myeloid and lymphocyte populations in the tumor microenvironment. J Immunother Cancer. 2014;2(suppl 3):P266.
- Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
- Schlegel RA, Williamson P. Phosphatidylserine, a death knell. Cell Death Differ. 2001;8:551-563.
- Wu Y, Tibrewal N, Birge RB. Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol. 2006;16:189-197.
- Maderna P, Godson C. Phagocytosis of apoptotic cells and the resolution of inflammation. Biochim Biophys Acta. 2003;1639:141-151.
- Ran S, Thorpe PE. Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy. Int J Radiat Oncol Biol Phys. 2002;54:1479-1484.
- Ran S, Downes A, Thorpe PE. Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res. 2002;62:6132-6140.
- Daleke DL. Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res. 2003;44:233-242.
- Huang X, Bennett M, Thorpe PE. A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice. Cancer Res. 2005;65:4408-4416.
- He J, Luster TA, Thorpe PE. Radiation-enhanced vascular targeting of human lung cancers in mice with a monoclonal antibody that binds anionic phospholipids. Clin Cancer Res. 2007;13:5211-5218.
- DeRose P, Thorpe PE, Gerber DE. Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment. Immunotherapy. 2011;3:933-944.
- Yin Y, Huang X, Lynn KD, et al. Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation. Cancer Immunol Res. 2013;1:256-268.
- He J, Yin Y, Luster TA, et al. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res. 2009;15:6871-6880.
- Belzile O, Zhang Z, Huang X, et al. Antibody-mediated blockade of phosphatidylserine combined with radiation improves survival and tumor eradication in a rat model of non-small cell lung cancer. Cancer Res. 2014;74(19 suppl). Abstract 639.
- Yin Y, Barbero G, Brownlee Z, et al. Targeting phosphatidylserine to improve androgen deprivation therapy of prostate cancer. Cancer Res. 2011;71(8 suppl). Abstract 621.
- Freimark B, Gong J, Ye D, et al. Antibody-mediated phosphatidylserine blockade significantly enhances the efficacy of immune blockade in K1735 and B16 mouse melanoma models. Cancer Res. 2015;75(15 suppl). Abstract 252.
- Altiok S, Mediavilla Varela M, Kreahling J, et al. Activation of CD8+ tumor infiltrating lymphocytes by bavituximab in a 3D ex vivo system of lung cancer patients. J Clin Oncol. 2015;33(suppl). Abstract 3060.
- Huang X, Gong J, Nguyen V, et al. Phosphatidylserine targeting antibody in combination with anti-PD-1 antibody treatment activates infiltrating T lymphocytes of the spleen and tumor microenvironment in pre-clinical models of melanoma and breast cancer. J Clin Oncol. 2015;33(suppl). Abstract 3059.
- Gong J, Nguyen V, Yin S, et al. Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in tumors. Cancer Res. 2014;74(19 suppl). Abstract 4978.
- Huang X, Yi Y, Barbero G, et al. Phosphatidylserine-targeting antibody synergizes with anti-PD-1 antibody to inhibit tumor growth in K1735 mouse melanoma model. Cancer Res. 2014;74(19 suppl). Abstract LB-262.
- American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.
- American Cancer Society. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Accessed August 16, 2015.
- Taxotere [Prescribing Information]. Bridgewater, NJ: sanofi-aventis; 2010.
- Fabbri F, Carloni S, Brigliadori G, et al. Sequential events of apoptosis involving docetaxel, a microtubule-interfering agent: a cytometric study. BMC Cell Biol. 2006;7:6.
- Gong J, Archer R, Brown M, et al. Measuring response to therapy by near-infrared imaging of tumors using a phosphatidylserine-targeting antibody fragment. Mol Imaging. 2013;12:244-256.
- Shtivelband M, Spigel DR, Gerber DE, et al. Randomized, blinded, placebo-controlled phase II trial of docetaxel and bavituximab as second-line therapy in locally advanced or metastatic non-squamous non-small cell lung cancer. J Clin Oncol. 2013;31(suppl). Abstract 8095.
- American Cancer Society. Lung Cancer (Non-Small Cell). www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-chemotherapy. Accessed August 24, 2015.
- Grilley-Olson JE, Villaruz LC, Stinchcombe TE, et al. A phase Ib study of bavituximab plus carboplatin and pemetrexed in chemotherapy naïve stage IV non-squamous non-small cell lung cancer. Presented at: Chicago Multidisciplinary Symposium on Thoracic Oncology; October 2014; Chicago, IL. Abstract 215.
- Digumarti R, Bapsy PP, Suresh AV, et al. Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer. Lung Cancer. 2014;86:231-236.
- Partridge AH, Rumble RB, Carey LA, et al. Chemotherapy and targeted therapy for women with human epidermal growth factor 2–negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.56.7479. Accessed August 28, 2015.
- Chalasani P, Marron M, Roe D, et al. A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer. Cancer Med. 2015;4:1051-1059.
- American Cancer Society. Survival rates for liver cancer. www.cancer.org/cancer/livercancer/detailedguide/liver-cancer-survival-rates. Accessed August 19, 2015.
- Nexavar [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.
- Llovet JM, Ricci S, Mazzaferro V, et al; for the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.
- Yopp AC, Singal AG, Arriaga YE, et al. A phase II study of bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2015;33(suppl). Abstract 4109.
- Koukourakis GV, Kouloulias V, Koukourakis MJ, et al. Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review. Molecules. 2008;13:
- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-2017.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
- Huang X, Gong J, Ye D, et al. Antibody-mediated phosphatidylserine blockade significantly enhances the efficacy of downstream immune checkpoint inhibition in K1735 mouse melanoma. J Immunother Cancer. 2014;2(suppl 3):205.
- Soria JC, Marabelle A, Brahmer JR, et al. Immune checkpoint modulation for non-small cell lung cancer. Clin Cancer Res. 2015;21:2256-2262.
- Opdivo [Prescribing Information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
Best Practices in Biomarker-Assisted Targeted Therapy in Lung Cancer: Lessons Learned From the Yale Cancer Center
Introduction The last decade has witnessed significant advances in the development of biomarkers in oncology that play a critical role in the understanding of molecular and cellular mechanisms that drive tumor initiation, maintenance, and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as investigators begin to [ Read More ]
Economic Burden of Inaccurate or Incomplete Hematologic Malignancy Diagnoses Optimal management of hematologic malignancies requires an early, accurate, complete, and clear diagnosis. Hematologic malignancies, however, are frequently misdiagnosed. Studies have demonstrated misdiagnosis in up to 27% of leukemia,1 18% of lymphoma,2 and 75% of Burkitt lymphoma2 cases. Often, there may [ Read More ]