Post-show wrap-up: Digging deep into IO at AACR
Coming away from the American Association for Cancer Research (AACR) annual meeting held in Washington, D.C., April 1-5, analysts at Leerink Partners who attended went back to their offices with one of their major takeaways being that immuno-oncology (IO) remains a major area of focus.
Emerging IO targets featured prominently in preclinical and early clinical work in particular, according to Leerink’s Dr. Michael Schmidt, Dr. Jonathan Chang and Dr. Varun Kumar, who wrote in a biopharma note shortly after AACR 2017, “We attended several presentations of groups working on emerging IO targets. [Bristol-Myers Squibb’s] IDO1 inhibitor looks slightly more potent than [Incyte Corp.’s] epacadostat and [Roche’s] GDC-919 preclinically. Whether this translates into a different clinical profile is unclear. The safety profile looked good so far in 44 patients treated in dose escalation and [Bristol-Myers Squibb] has expanded three of eight planned cohorts thus far with anecdotal efficacy reported in three patients.”
In a news release, Bristol-Myers Squibb noted in part of its IDO1 inhibitor (dubbed BMS-986205) that in-vitro characteristics included potent inhibition of kynurenine production in IDO1-HEK293 cells but not in TDO-HEK293 cells, sustained inhibition in IDO1 cell-based assays after washout and single-digit nM potency in human tolerogenic mixed lymphocyte reaction assays. Based on preclinical data, a 150 mg daily human dose was projected to maximally inhibit IDO1.
The Leerink analysts also noted NewLink Genetics Corp.’s reported efficacy results of its IDO pathway inhibitor indoximod in combination with Keytruda in 60 patients treated with melanoma in a Phase 1 trial, which indicated the overall response rate (ORR) coming in at 59 percent and complete response (CR) rate coming in at 12 percent, slightly below that of Incyte’s epacadostst/Keytruda combination reported at the recent European Society for Medical Oncology meeting (58 percent ORR, 26 percent CR rate).
“[The] main unresolved question according to the AACR discussant is how (or if) [NewLink’s] compound actually works given that it doesn’t affect kyneurinine levels, a key PD (pharmacodynamic) marker of IDO inhibition, and how it could best be developed given the competition,” they wrote.
Corvus Pharmaceuticals’ first-in-human Phase 1 trial of A2aR antagonist CPI-444, the analysts noted, “was met with disappointment among investors, given the low rate of responses seen (3/96) in patients who received single-agent CPI-444 or atezolizumab combination therapy.”
Meanwhile, Roche highlighted the strong preclinical rationale of combining its anti-CSF1R (emactuzumab) with its anti-CD40 agonist in a recently initiated second combination clinical trial in addition to atezolizumab. Also, Five Prime Therapeutics highlighted several preclinical presentations providing a rationale for combining its cabiralizumab (an anti-CSF1R agent) with Opdivo. Data from the ongoing Phase 1b combination trial is expected in the latter half of this year.
“We have generated a comprehensive library of essentially all human extracellular proteins and have used this library to screen for new agents that modulate the function of various immune cell subsets,” said Dr. Luis Borges, senior vice president of research at Five Prime. “Taken together, we have developed robust in-vitro and in-vivo platforms that allow us to discover new immuno-oncology targets that we believe will help address the needs of cancer patients who fail to respond to current immunomodulatory therapies.”
In other news, Memorial Sloan Kettering Cancer Center’s TRX-518, the Leerink analysts wrote, “remains the only GITR agonist with clinical data presented to date, but the AACR presentation looked similar to recent SITC (Society for Immunotherapy of Cancer meeting) slides, which only contained PD data (T-reg reduction).”
Among other highlights the analysts noted: Calithera Bioscience’s collaborators presented preclinical data from the company’s glutaminase inhibitor (CB-839) that indicated a need to combine it with other agents; preclinical data from OncoMed Pharmaceutical’s anti-TIGIT supports the mechanism of this new immune checkpoint inhibitor; and Celgene Corp. presented for the first time preclinical data from its anti-CD47, indicating dose-dependent antitumor activity in animal models, while lacking red blood cell binding.
Other IO players
Some of the other companies delving into immuno-oncology that sent news releases to DDNews post-AACR were amcure, Exscientia, OSE Immunotherapeutics and Siamab.
With regard to amcure, the company noted that it had presented in-vivo and in-vitro data on its lead development candidate, AMC303, at AACR 2017, with a poster presentation highlighting AMC303’s “unique and novel mode of action which inhibits CD44v6 and, therefore, signals three cancer relevant receptor tyrosine kinases: c-MET, RON and VEGFR-2.” According to amcure, data generated with AMC303 indicate that it combines a strong antitumor and antimetastatic effect and that in a pancreatic tumor mouse model, a three-week treatment with AMC303 resulted in a clear inhibition of tumor growth and metastasis formation as well as a marked reduction of preformed metastases.
AMC303 is currently being evaluated in a Phase 1/1b clinical study as a monotherapy in patients with advanced metastatic malignant solid tumors of epithelial origin, such as pancreatic, head and neck, colorectal, gastric and lung cancer.
Exscientia, which calls itself “an innovative company at the forefront of artificial intelligence-driven drug discovery,” announced that the latest results of its collaboration with Evotec to develop adenosinergic small molecules focused on immuno-oncology were presented at AACR 2017. Highlights of the poster included presentation of a selective adenosine 2A receptor (A2AR) antagonist, currently being explored for candidate selection, as well as first demonstration of a bispecific small molecule (a single, low-molecular-weight compound with dual pharmacology) capable of simultaneously antagonizing A2AR and inhibiting CD73.
According to Exscientia, “These results represent rapid progress in a timeframe of less than 12 months since the announcement of this partnership in April 2016. The adenosine pathway is one of the main drivers of tumor progression by acting on two key features of the tumor micro-environment: evasion of the host immune system and angiogenesis. Expression of CD73 on tumor cells and on immunosuppressive cell subsets leads to the generation of adenosine. Adenosine inhibits the biological functions of T lymphocytes infiltrating the tumor by binding to A2AR.”
OSE Immunotherapeutics presented what it called “significant results” at the AACR meeting, “in the very promising field of myeloid/macrophage suppressive cells, an abundant immune cell type infiltrating many tumors and often associated with a poor prognosis.”
OSE-172 (Effi-DEM) is a first-in-class checkpoint inhibitor that blocks these suppressive cells, allowing parallel mobilization of T cells and—according to data so far—producing antitumorigenic results in monotherapy and in combination with other immunotherapies like T checkpoint inhibitors.
OSE-172 is a selective SIRP-alpha antagonist monoclonal antibody. SIRP-alpha is expressed on myeloid suppressive cells (primarily on myeloid-derived suppressor cells [MDSCs] and tumor-associated macrophages). The main ligand of SIRP-alpha is CD47, which is ubiquitously expressed in various cells and overexpressed in tumors.
CD47 is said to interact with several other ligands and physiological functions, such as the CD47/SIRP-gamma axis, another member of the SIRP family, which has been observed to play a role in human T cell proliferation, OSE noted. OSE-172 is not a binder of SIRP-gamma, thus avoiding a deleterious impact on T cell immune response and allowing for a strong human effector T cell proliferation—a key advantage of this mechanism of action, according to the company.
“These new data demonstrate OSE-172 as having a differentiated safety and selective pharmacological profile, which provides us with the opportunity to open various potential indications in the immuno-oncology field for our new myeloid checkpoint inhibitor,” said Bernard Vanhove, OSE’s chief operating officer in charge of R&D and international scientific collaborations. “We are currently actively preparing the next steps of its development towards clinical stage.”
Finally, Siamab Therapeutics Inc. announced the presentation of two posters featuring new preclinical data for its novel anti-Sialyl-Tn (STn) antibodies, antibody-drug conjugates (ADCs) and anti-STn, anti-CD3 bispecific antibodies. The findings highlight Siamab’s two-pronged approach to develop antibody therapeutics using both ADCs and bispecific antibodies to target STn, a tumor-associated carbohydrate antigen (TACA), and induce immune response to destroy tumor cells. The company’s lead program, ST1, is in late-stage preclinical development and is expected to enter human clinical trials in 2018.
Siamab is leveraging its proprietary technology platform to discover and develop monoclonal antibody (mAb) therapeutics that bind to TACAs, a novel class of cancer-specific targets that are implicated in immune suppression, chemoresistance and a cancer stem-cell phenotype. The company call STn “an exciting TACA target with high cancer specificity, which is rarely expressed in normal tissues.”
STn is highly expressed in numerous human adenocarcinomas, including ovarian, pancreatic, prostate, colon, gastric and breast cancers. STn expression has been linked to innate immune suppression, a chemoresistant stem-cell phenotype, invasion/metastasis and poor prognosis. MDSCs, the company noted, are a population of immature myeloid cells that have undergone aberrant differentiation in the tumor and play a critical role in actively blocking T cell activation in the tumor microenvironment. Both myeloid and granulocytic MDSCs express STn antigens.
“We are pleased to present this new data at AACR highlighting our antibody drug development strategy using ADCs and bispecific antibodies to target STn, an intriguing cancer biomarker and therapeutic target,” said Jeff Behrens, president and CEO of Siamab, in a news release before the presentation. “Our data show that manipulating STn biology in a variety of cancers offers the potential to generate significant immune re-engagement and antimetastatic therapeutic benefits. In particular, we are very encouraged by our findings demonstrating that MDSCs express STn and therefore have the potential to be targeted with our antibody-based therapies to provoke an antitumor immune response. We are also encouraged by our proof-of-concept study data showing that our anti-STn, anti- CD3 bispecific antibodies are highly specific to both tumor and T cells and demonstrate strong efficacy in vitro.”
3D tumor models
Stepping away from IO candidates and research for a moment, it is also worth noting that at AACR 2017, the inaugural meeting of the 3D Standards Working Group was held. Organized and hosted by the National Center for Advancing Translational Sciences (NCATS), part of the U.S. National Institutes of Health, along with InSphero AG, the meeting drew representatives from academic institutions, pharmaceutical and life-sciences industries—as well as government agencies—to discuss the use of 3D cancer models within drug discovery campaigns and review biological and technical requirements needed for the next-generation of high-throughput screening-compatible models.
“There is a growing need for in-vitro 3D tumor models that mimic in-vivo tumor physiology for more efficient cancer drug discovery,” said InSphero Chief Scientific Officer Dr. Patrick Guye. “We sought to bring together key opinion leaders in academia, industry and government to develop guidelines that we believe are critical to establish 3D tumor models as a highly predictive platform for therapeutic drug development assays.”
The group plans to publish its findings and recommendations for developing and using 3D tumor models for drug development, with the intent to make the best consensus information available to the broader research community.
“We made tremendous progress during this kickoff meeting,” according to Dr. Madhu Lal Nag, head of the Trans-NIH RNAi facility at NCATS. “We not only discussed where we stand today with regard to developing advanced 3D models that capture the complexity of the tumor microenvironment, but also delved into needs for standardized nomenclature, benchmarking, improved model predictivity and multiparametric readouts.” Going forward, the group plans to meet quarterly by teleconference and in person during future conferences, such as AACR, which most members of the working group attend.
Managing severe side effects of CAR-T cell treatment
WEST LAFAYETTE, Ind.—Endocyte Inc., a leader in developing targeted small-molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy, noted a late-breaking poster session at AACR 2017 on the presentation of new research from investigators and faculty at the Purdue University Center for Drug Discovery that applies Endocyte’s SMDC technology in a chimeric antigen receptor (CAR) therapy setting.
“The significant potential of CAR-T cell therapies has been limited by an inability to control the rate and degree of cytokine release, which can cause severe safety issues in patients. The data presented demonstrate approaches that may successfully mitigate these cytokine storms and highlight how Endocyte’s bi-specific SMDC adaptors can potentially improve the safety and tolerability profiles of current CAR-T cell therapies,” said Mike Sherman, president and CEO of Endocyte. “This is just one example of how we are continuing to advance our next-generation CAR-T cell therapeutic platform, now also in collaboration with leading experts in the field at Seattle Children’s Research Institute.”
The presentation discussed methods in which Endocyte’s bi-specific SMDC adaptors can control the rate and extent of CAR-T cell activation, by using a bispecific adaptor molecule to mediate engagement of the CAR-T cell with the cancer cell. Endocyte’s unique bispecific adaptors are constructed with a fluorescein isothiocyanate (FITC) molecule and a tumor-homing molecule to precisely bridge a universal CAR-T cell with the cancer cells, which causes localized T cell activation. This approach reportedly enables a universal CAR-T -cell to bind and kill a cancer cell only when the bispecific adaptor establishes a bridge between the two.
“We are very pleased with the results of these studies, as they confirm our hypothesis that the use of bi-specific SMDC adaptors can offer a next-generation approach to CAR-T cell therapy. We look forward to continuing our research, including exploring the ability of this approach to more completely target cells in heterogeneous solid tumors,” said Dr. Phil Low, a professor of chemistry and director of the Center for Drug Discovery at Purdue University. Low is the chief scientific officer, a board member and founder of Endocyte.
Endocyte and Purdue University have exclusive agreements to research, develop and commercialize SMDC therapeutics and companion imaging agents for the treatment of disease through a long-standing partnership with Low and Purdue University. Those agreements grant Endocyte exclusive rights to the CAR-T cell and SMDC adaptors for all indications. This technology is jointly owned by Endocyte and Purdue and is covered by pending patent applications.
Bavituximab could enhance antitumor activity of immunotherapy
TUSTIN, Calif.—Peregrine Pharmaceuticals Inc. announced at AACR 2017 results of a new analysis of the Phase 3 SUNRISE trial of bavituximab in patients with previously treated locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Data demonstrated that for patients in the study’s bavituximab plus docetaxel treatment arm who received subsequent immunotherapy, the median overall survival (mOS) was not reached, while mOS was 13 months for patients in the study’s placebo plus docetaxel arm who received subsequent immunotherapy. These are the first clinical results reported supporting the hypothesis that bavituximab may modulate the tumor microenvironment to enhance the antitumor activity of immunotherapy agents.
The presentation highlighted an analysis in which the company evaluated the impact of subsequent immunotherapy treatment, as well as patients’ pre-treatment interferon gamma (IFN-γ) levels on overall survival. Overall, low peripheral IFN-γ correlated with more favorable OS in the patients receiving bavituximab plus docetaxel, and it is a biomarker of interest. Data were also analyzed by low vs. high IFN-γ levels. For patients with low pre-treatment IFN-γ levels who received subsequent immunotherapy, those in the bavituximab plus docetaxel arm did not reach mOS compared to mOS of 12.1 months for the placebo plus docetaxel arm.
“We are extremely encouraged by the results of these exploratory analyses, which provide further clinical rationale for combining bavituximab and checkpoint inhibitors,” said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. “This will be the key focus for upcoming early phase clinical trials, which includes a study of bavituximab and pembrolizumab in head and neck cancer through our ongoing collaboration with the National Comprehensive Cancer Network.”
Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. PS-targeting antibodies have demonstrated an ability to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. Bavituximab is believed to override PS immunosuppressive signaling by blocking the engagement of PS with its receptors and sending an alternate immune activating signal. Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments.
Seattle Genetics presents data advancing ADC and novel immuno-oncology programs
BOTHELL, Wash.—Seattle Genetics Inc. highlighted at AACR 2017 multiple data presentations that support the company’s advancing antibody-drug conjugate (ADC) and immuno-oncology programs. The presentations described the ability of Adcetris (brentuximab vedotin) to, for example, activate antitumor immune responses, supporting continued clinical evaluation in combination with checkpoint inhibitors.
Additionally, preclinical data feature two immuno-oncology agents, SEA-CD40 and SGN-2FF, both of which are in Phase 1 trials. Seattle Genetics and Unum Therapeutics presented preclinical data evaluating combination treatment with antibody-coupled T cell receptor (ACTR)-engineered autologous T cells and an antibody targeting B-cell maturation antigen (BCMA), SEA-BCMA, for multiple myeloma. Further data highlighted clinical biomarker analyses for vadastuximab talirine (SGN-CD33A; 33A), an ADC under evaluation in the global Phase 3 CASCADE trial for acute myeloid leukemia.
“Our expertise in empowered-antibody innovation drives a substantial, advancing pipeline of more than a dozen clinical and preclinical programs, both ADCs and immuno-oncology agents,” said Dr. Jonathan Drachman, chief medical officer and executive vice president of research and development at Seattle Genetics. “Preclinical data presented at AACR support multiple ongoing clinical studies evaluating combination treatment of Adcetris and nivolumab (Opdivo) in relapsed Hodgkin and non-Hodgkin lymphoma and Phase 1 trials of two proprietary immuno-oncology agents, SEA-CD40 and SGN-2FF, in solid tumors. Seattle Genetics is transforming into a global, multi-product oncology company through dedication to scientific innovation and the needs of patients.”
Proof of concept data for larotrectinib in TRK fusion glioblastoma
STAMFORD, Conn.—Loxo Oncology Inc. presented data on larotrectinib (LOXO-101) in an abstract and poster that described initial clinical data across the larotrectinib program for all patients with TRK fusion primary central nervous system (CNS) cancers. The cases included three patients with glioblastoma: one patient treated under an expanded access protocol and two patients treated in the ongoing Phase 2 NAVIGATE trial.
In the cases described, larotrectinib showed preliminary evidence of antitumor activity. The expanded access patient, described in detail in the abstract, had progressed through prior radiation, temozolomide and bevacizumab, and that patient demonstrated a brief mixed radiographic response on larotrectinib in the context of a molecularly complex tumor (select regions of the tumor harbored a TRK fusion, while others did not).
The two patients treated in NAVIGATE, described in the poster, were enrolled following progression on chemoradiation and temozolomide (both cases) and bevacizumab (one case). The NAVIGATE patients remain on therapy at four months with radiographic evidence of treatment effect, as of a March 13, 2017, data cutoff date.
Glioblastomas are highly aggressive CNS tumors, particularly in the post-bevacizumab setting where median overall survival is typically three to six months. Global regulatory discussions have established that primary CNS tumors, including glioblastoma, will not be included in the primary efficacy analysis dataset intended to support initial drug approval, though they are being enrolled in a dedicated treatment arm of NAVIGATE.
“Glioblastomas have historically defied rational targeted therapy approaches, so we are encouraged that larotrectinib may have a role in treating TRK fusion presentations of this devastating disease. We hope these early data lead to increased molecular profiling and referrals to appropriate clinical trials,” said Dr. Josh Bilenker, CEO of Loxo Oncology. “We knew it would be necessary to evaluate these patients separately from our primary efficacy dataset, which relies on a RECIST overall response rate primary endpoint. Given the limitations around response assessment in neuro- oncology, randomized survival trials remain the gold standard for evaluating new drugs in primary CNS cancers. However, patients with systemic tumors that have metastasized to the brain are included in our primary efficacy dataset, though they have been exceedingly uncommon. As illustrated in our adult Phase 1 dataset and this AACR poster, we are pleased with larotrectinib’s ability to enter the CNS in a tolerated fashion and address TRK fusion tumors.”
Leap presents nonclinical and Phase 1 data for TRX518 and DKN-01
CAMBRIDGE, Mass.—At AACR 2017, Leap Therapeutics Inc. reported nonclinical and clinical data for its GITR agonist antibody, TRX518, and its Dickkopf-1 inhibitor antibody.
Dr. Roberta Zappasodi, research scholar at Memorial Sloan Kettering Cancer Center, led an oral presentation during the clinical trials plenary session titled “Intratumor and peripheral Treg modulation as a pharmacodynamic biomarker of the GITR agonist antibody TRX-518 in the first-in-human trial.”
Zappasodi presented updated data on clinical biomarkers and the mechanism of action of TRX518. The data were generated in the Merghoub and Wolchok group in the Ludwig Collaborative, Parker Institute and Swim Across America Lab at Memorial Sloan Kettering Cancer Center. Dr. Taha Merghoub, is associate attending laboratory member in the Melanoma and Immunotherapeutics Service and Dr. Jedd Wolchok, is chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center.
Data from the TRX518 Phase 1 trial showed that a single-dose of TRX518 was associated with a reduction in immunosuppressive regulatory T cells in patients’ tumors and in circulating blood. Further analysis in donor blood samples in vitro showed that TRX518 induces T-Bet upregulation and increases cell death in regulatory T cells.
“These clinical data further demonstrate a direct effect of GITR stimulation with TRX518 on human regulatory T cells. As such, GITR stimulation may be an important therapeutic tool to generate antitumor immunity, to be considered for future immune therapy-based combination trials,” said Merghoub.
TRX518 is a humanized monoclonal antibody with agonist activity targeting glucocorticord-inducible TNF-superfamily receptor (GITR). TRX518 is engineered to enhance immune responses to cancer. TRX518 is being studied in two ongoing repeat-dose clinical trials in patients with advanced solid tumor malignancies.