A number of new clinical and pre-clinical agents currently in development were explored during the SITC 31st Annual Meeting and Associated Programs.
Which are the most logical, most interesting, and most promising of those projects? A panel of experts considered more than 60 possibilities when putting together the “New Cancer Immunotherapy Agents in Development” session for the Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting and Associated Programs.
“What we’re offering is essentially a speed-dating event for some of the novel combinations that we find most exciting. Presentations will only run 5 minutes, so audience members can get a taste of what’s out there in this first session of the conference,” said session co-chair Ramy Ibrahim, MD, vice president for Clinical Development at the Parker Institute for Cancer Immunotherapy in San Francisco.
Ibrahim and his co-chairs concentrated on what they believe to be the most exciting area of immunotherapy research: novel combinations. They were particularly keen on those that combined different immunotherapies with each other.
“Is it possible that some new agent will come along and prove itself powerful enough to cure all sorts of tumor types as monotherapy? Certainly. It seems a lot more likely, though, at least in the foreseeable future, that the key to maximizing the benefit from new medications will lie in combining those medications effectively with each other and with older medications,” said another of the panel’s co-chairs, Daniel S. Chen, MD, PhD, vice president and global head of Cancer Immunotherapy Product Development at Genentech and Roche.
The session will be divided evenly between presentations that discuss the results of very early clinical trials and those that discuss the results of pre-clinical investigations. Many of the experimental combinations employ the relatively small number of immunotherapies that have already been approved by the FDA, but many others use experimental immunotherapies, either in combination with those that are already approved or with other agents.
“Together, the presentations should illustrate how much diversity there is in immunotherapy research. Researchers are using different approaches to augment the immune response against cancer,” Ibrahim said. “However, amid all the diversity, there is a unifying principle: synergy. We tried to steer clear of combinations that merely add immunotherapy to some existing regimen. We focused instead on combinations designed with the potential that each agent will strengthen the others and create a whole that’s better than the sum of its parts.”
Anti-Semaphorin4D VX15/2503 in Combination with Ipilimumab or Antibody to PD-1 or PD-L1
Presented by: Elizabeth Evans, PhD, Vaccinex, Inc.
The protein Semaphorin 4D (SEMA4D) is highly expressed at the growing invasive margins of tumors, where it restricts the infiltration and migration of anti-tumor immune cells, such as antigen presenting cells and T lymphocytes, into the tumor microenvironment, indicating its role in promoting tumor growth. Investigators evaluated anti-SEMA4D anti bodies alone and in combination with antibodies against immune checkpoints in pre-clinical and phase I trials, which found that anti-SEMA4D antibodies were welltolerated in patients with advanced refractory solid tumors. In pre-clinical trials, antibody blockade of SEMA4D activity facilitated increase in the antitumor immune response through recruitment of activated antigen presenting cells and T lymphocytes, as well as a shift in proinflammatory cytokines within the tumor microenvironment. Results were even better when investigators added the second immunotherapy. The combination of antiSEMA4D with antiCTLA-4 (ipilimumab) acted synergistically, with a maximal increase in survival (P<0.01) and complete tumor regression in 100% of mice compared with 22% of mice treated with monotherapy (P<0.01). Phase Ib/IIa trials are planned to investigate the combination of anti-SEMA4D and immune checkpoint inhibitor therapies.
Cobimetinib in Combination With Atezolizumab
Presented by: Edward Cha, Genentech
Engagement of the Toll-like receptor 9 (TLR9) stimulates mature antigen presenting cells, namely dendritic cells, and improves T cell priming for antitumor immunity. Investigators reasoned that in patients with metastatic melanoma resistant to PD-1 blockade therapy, intratumoral injections of the combination treatment with an experimental TLR9 ago nist, IMO-2125, given in conjunction with the immune checkpoint inhibitor, ipilimumab, therapy will induce tumor-specific effector T cells for generating an antitumor response and overcoming tumor immune-escape. According to the latest abstract, only 11 patients have been enrolled in the phase I trial, which has yet to observe any dose-limiting toxicities associated with the IMO-2125 injections. The only immune-related adverse event (AE) observed was grade 3 hypophysitis in 2 patients. Of the 5 patients enrolled long enough for a very early evaluation, 2 experienced partial remission, 2 experienced stable disease (SD), and 1 experienced progressive disease (PD). A phase II expansion will use IMO-2125 in combination with ipilimumab and an antiPD-1 treatment. Updated data on safety, antitumor activity, and biomarkers will be presented during the session.
IMO-2125, an Investigational Intratumoral Toll-Like Receptor 9 Agonist, Modulates the Tumor Microenvironment to Enhance Antitumor Immunity
Presented by: Mark Cornfeld, MD, MPH, Idera Pharmaceuticals
Dysfunctional regulation of the mitogen-activated protein kinase (MAPK) signaling network is associated with cancer cell survival and proliferation. In BRAF-mutated melanoma and KRAS/BRAF-mutated colorectal cancer, gain-of-function mutations to these oncogenes contributes to the over activity of downstream mitogen-activated protein kinase enzyme (MEK) within the signaling cascade leading to the transcription of genes mediating cancer cell survival. The MEK inhibitor cobimetinib (Cotellic), which is already approved against melanoma, was tested in conjunction with the PD-L1 inhibitor atezolizumab (Tecentriq) in a phase Ib trial on 23 patients with microsatellite stable colorectal cancer. Although study patients had received an average of 5 prior treatment regimens, investigators reported this summer that 4 of the patients achieved partial responses (PRs) and 5 more showed SD. It is the first study to show a response to either PD-1/PD-L1 blockade or an MEK inhibitor in patients with microsatellite stable colorectal cancer, which is far more common than the microsatellite instability-high colorectal cancer that responded to such immunotherapy in previous studies. The 4 patients who achieved PRs all saw their tumors shrink by at least 30%. Responses lasted for more than a year in some patients and were still going on when researchers first reported the data.
Combination Strategy for Varlilumab, an Agonist AntiCD27 Monoclonal Antibody
Presented by: Thomas Davis, MD, Celldex
Varlilumab is a human monoclonal antibody targeted to the CD27 receptor expressed on lymphocytes, and is highly expressed on T and B lymphoma tumor types. Varlilumab binds and activates CD27 as the potent co-stimulatory signal for activation and proliferation of T cells when combined with T-cell receptor stimulation to enhance immune response and anti-tumor activity. Atezolizumab is a mAb which binds PD-L1 on tumor-infiltrating immune cells and tumor cells, inhibiting the PD-L1/PD-1 mediated escape of tumors from immune surveillance. The use of this immunotherapy combination in preclinical tumor models resulted in significant increases in survival (compared to atezolizumab alone) in a CT-26 colon model, an E.G7 thymoma model, and a BCL1 disseminated lymphoma model. The strength of those findings led, last December, to the initiation of a phase I/II study of varlilumab in combination with atezolizumab in patients with renal cell carcinoma. Results have already been reported on the phase I portion of a phase I/II study of varlilumab and nivolumab.
Among the 36 patients in that part of the study, the combination showed acceptable tolerability and safety at all dosing levels and no evidence of an autoimmune reaction. Biomarker data from all varlilumab dose levels indicated increases in inflammatory chemokines and decreases in circulating T regulatory cells. Seven patients achieved stable or better disease during the trial. “Varlilumab is an attractive candidate for combination immunotherapy across a variety of cancers due to its target’s restricted expression and strong activity in a variety of tumor models,” Davis said.
Safety of the Natural Killer Cell-Targeted Anti-KIR Antibody, Lirilumab, in Combination with Nivolumab or Ipilimumab in 2 Phase I Studies in Advanced Refractory Solid Tumors
Presented by: F. Stephen Hodi, MD, Dana-Farber Cancer Institute
Lirilumab is a checkpoint inhibitor designed to activate natural killer (NK) cells (and potentially some types of T cells) by blocking interaction between killer-cell immunoglobulin-like receptors (KIRs) and their ligands. Results from the phase I trial that combined lirilumab and nivolumab reported treatment-related AEs in 114 of 159 participating patients and grade 3/4 events in 24 of them. Results from the phase I trial that used lirilumab in combination with ipilimumab in patients with various solid tumors reported treatment-related AEs in 15 of the 22 patients who participated and grade 3/4 events in 2 of them. Although the rate of AEs (and serious AEs) was lower with the ipilimumab combinationindeed, it was about the same as that of ipilimumab monotherapy—Bristol-Myers Squibb has announced that it will stop investigating that combination while it continues investigating the nivolumab combination. This may be because of unreported data about antitumor activity from the 2 combinations. Bristol-Myers plans to report data on the lirilumab and nivolumab combination in a separate release.
A CD122-Biased Agonist Increases CD8+ T Cells and Natural Killer Cells in the Tumor Microenvironment; Making Cold Tumors Hot With NKTR-214
Presented by: Adi Diab, MD, The University of Texas MD Anderson Cancer Center
NKTR-214 binds and activates the CD122 cell surface receptor expressed on tumor-infiltrating lymphocytes. The breakdown of PEGylated NKTR-214 causes the release of active IL-2 conjugates to antagonize CD122. This provides sustained activation of the IL-2 pathway through controlled release of active CD122-biased (IL-2Rβɣ) cytokines. Preclinical studies have found that NKTR-214, used alone or as combination immunotherapy with other checkpoint inhibitors, significantly suppressed tumor growth through increased proliferation and migration of effector CD8+ T cells and NK cells within the tumor microenvironment. The abstract showed very early results from a phase I trial. As of August, 18 patients with locally advanced or metastatic solid tumors were enrolled, 12 of whom have renal cell cancer. Among the 12 patients who had been participating long enough for evaluation, 7 patients had SD at their 6-week or 8-week scan. Only 1 patient had experienced dose-limiting toxicity from NKTR-214 (grade 3 syncope and hypotension). Tumor biopsies were conducted in 9 patients, and 6 of those patients’ tumors revealed an up to 10-fold increase from baseline in CD8+ T cells and NK cells in the tumor microenvironment. Most of the infiltrating CD8+ T cells were newly proliferative and cell-surface PD-1 expression was increased up to 2-fold. Analyses of blood samples showed concordant increases in Ki67+ immune cells, PD-1+ CD8+ T cells, and NK cells 8 days after a single dose of NKTR-214. Updated data was presented during the session.
Activated Natural Killer Cell Therapy
Presented by: Patrick Soon-Shiong, MD, FRCS, FACS, Nantbioscience
A pair of experimental immunotherapies from Altor BioScience are undergoing a wide range of early-stage clinical trialsas both monotherapy and combination therapy—against metastatic melanoma, metastatic urothelial cancer, and other tumor types. ALT-801 is a fusion protein consisting of interleukin-2 (IL-2), and a single-chain T-cell receptor domain. Preclinical trials have shown that this combined molecule stimulates more immune response against both solid and hematological malignancies than IL-2. ALT-803 is a novel mutant of IL-15 that is both more stable than the normal strain and better at triggering the proliferation and activation of NK cells and CD8+ memory T cells. It is currently undergoing 7 phase I trials and 1 phase II trial in patients with a wide variety of cancers, as well as patients with HIV. A recently announced collaboration between Altor and NantKwest will likely see both of those treatments paired with NantKwest’s NK cell therapy.
CD3-EGFR Probody T Cell- Engaging Bispecific Induces Tumor Regressions and Substantially Increases Safety Window in Preclinical Studies
Presented by: Bryan A. Irving, PhD, Cytomx Therapeutics
Many immunotherapies make the body attack tumors by binding to antigens that are abundantly expressed on tumors and preventing those antigens from blocking immune system attacks. Unfortunately, those same therapies can bind to those same antigens on healthy cells and lead the body to attack them, as well. CytomX Therapeutics hopes to change that with technology that can render immunotherapies (mostly) inactive, except when they’re in the presence of a tumor. Research in mice has shown that a “Probody” version of a PD-1 immunotherapy works about as well as the standard version but produces fewer side effects. Indeed, a CTLA-4/PD-1 antibody combination induced diabetes in 50% of non-obese young mice but the substitution of the Probody PD-1 formulation in another mouse cohort eliminated the incidence of diabetes. CytomX believes that its technology for making Probody versions of individual compounds will work on a wide range of immunotherapies with different targets and different biological pathways.
PRS-343, a CD137 (4-1BB)/ HER2 Bispecific
Presented by: Shane A. Olwill, PhD, Pieris Pharmaceuticals, Inc.
CD137 is a costimulatory immunoreceptor expressed on T cells, dendritic cells, and NK cells. Many studies have shown the ability of CD137-activating compounds to spur strong immune responses against tumors. Unfortunately, such compounds have also spurred immune responses against healthy cells. PRS343 was designed as a protein with CD137targeting fused to a variant of a trastuzumab (Herceptin) HER2-targeting monoclonal antibody with an IgG4 protein backbone. Ex vivo experiments have previously shown that the compound can activate T cells in the presence of HER2+ cells. More recently, studies have shown that it can do the same in a humanized murine model. PRS-343 activity was investigated at 4 different weekly doses, ranging from 4µg to 200µg. Investigators found that PRS-343 dose dependently led to strong tumor growth inhibition compared with treatment with the isotype control. Tumor response was accompanied by a significantly higher frequency of hCD45(+) tumor infiltrating lymphocytes due to proliferation of CD3+ and CD8+ T cells.
pLADD: Personalized, Live, Attenuated Double-Deleted Listeria Monocytogenes
Presented by: Thomas W. Dubensky Jr., PhD, Aduro Biotech
Today’s immunotherapies target standard proteins that exist in both tumors and healthy cells, but what if it were possible to develop customized immunotherapies that were designed to attack the mutations in each patient’s cancer? Such treatments, in theory, should lead the immune system to attack tumors without attacking healthy cells, as well. They’re already being tested. Aduro used tumor-specific neoepitopes from murine MC38 tumor cells to formulate a personalized live, attenuated double-deleted Listeria monocytogene (pLADD). Administration of pLADD-MC38 in mice induced cellular immune responses against encoded neoepitopes but not against native sequences. Moreover, investigators found a synergistic antitumor efficacy with pLADD-MC38 and antiPD-1. The FDA has given its approval for a phase I study and Dubensky discussed its progress to date.
CA170: A Small Molecule Orally Available Checkpoint Inhibitor
Presented by: David Tuck, MD, Curis
Checkpoint inhibitors have achieved impressive results in the battle against many tumors, but all currently available options have major drawbacks. They work in a relatively low percentage of patients because they target only a single pathway. Their long half-lives can trigger immune-related adverse events. They’re all complex intravenously administered proteins that are difficult (and expensive) to manufacture. CA170 is an attempt to solve all of those prob lems at once: it’s an oral small molecule with a short half-life that inhibits the PD-1/PD-L1/2 and VISTA/PD-1H immune checkpoint pathways. Tested in cell cultures, it shows as much immune activity as antibody treatments. In immune competent mice, moreover, orally administered CA-170 has been found to inhibit the growth of syngeneic tumors, enhance peripheral T-cell activation, and promote the immune activation of tumor infiltrating CD8+ T cells in a dose-dependent manner. The compound also shows no signs of toxicity in safety trials.
LAG-3Ig (IMP321) in Combination With Anti-PD-1 Therapy
Presented by: Frederic Triebel, MD, PhD, Prima Biomed
Lymphocyte Activation Gene-3 (LAG-3 or CD223) is a cell surface protein that regulates signaling between antigen presenting cells and T cells in the immune response. In some conditions, it activates antigen presenting cells and increases the activity of CD8+ T cells, leading to enhanced immune response. However, LAG-3 can also act as a co-inhibitory receptor on the surface of activated T cells following antigen recognition and T-cell receptor stimulation, leading to a decrease in cytokine production and immune response. The experimental treatment IMP321 is a soluble dimer of LAG-3 that has been shown to induce immune responses in cancer patients through potent activation of antigen presenting cells. Investigators hope the treatment, which stimulates antigen presenting cells, will prove particularly effective when used with chemotherapy, which induces dying cancer cells to give off antigens. The compound has undergone several early trials to date and shown itself to be well tolerated. Prima Biomed says that repeated daily injections “have been able to demonstrate the induction of a sustained (eg, lasting over several months) APC activation and memory CD8 T-cell response in patients.”
Agent APD-1 DNR-41BB: Converting Tumor-Mediated PD-L1 Inhibition Into CAR T-Cell Co-stimulation
Presented by: Prasad S. Adusumilli, MD, FACS, FCCP, Memorial Sloan Kettering Cancer Center
Following an immune attack, solid tumors upregulate co-inhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T-cell therapies, which redirect T cells to solid tumors. Investigators used an orthotopic mouse model of pleural mesothelioma to investigate various strategies for overcoming the inhibition of CAR T cells. They found that high doses of both CD28- and 4-1BBbased second-generation CAR T cells achieved tumor eradication. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. Furthermore, PD-1/PD-L1 pathway interference restored the effector function of CD28 CAR T cells. These findings suggest that PD-1/ PD-L1 blockade may be an effective strategy for improving the potency of CAR T-cell therapies.
The Immunoreceptor TIGIT Regulates Antitumor Immunity
Presented by: Jane Grogan, PhD, Genentech
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a dominant co-inhibitory receptor on tumor specific T cells and NK cells, and is co-expressed with other checkpoint immune receptors such as PD-1. TIGIT and CD226 on these tumor-specific T cells compete for binding to the PVR ligand on tumor cells. Upon binding to PVR, TIGIT receptor activation induces inhibitory signaling, which limits proliferation, effector cytokine production, and the killing of target tumor cells. Investigators used antibody blockade of TIGIT, CD226, and PD-L1 in syngeneic murine models of colorectal cancer and observed co-blockade of TIGIT and PD-L1 enhanced CD8+ T-cell effector function that produced significant tumor clearance. Specific ablation of TIGIT on CD8+ T cells resulted in tumor clearance, and was dependent on PVR in the host tissue. Models indicate that inhibition of TIGIT with a blocking monoclonal antibody may release CD226 to activate tumor-specific T cells. As TIGIT was found to be expressed on Treg cells, CD8+ T cells, and NK cells, another mechanism could involve regulation of T cell suppression by TIGIT on Tregs. Phase I clinical trials are underway.
The session ended with a 25-minute question-and-answer period, designed to give audience members a chance to dive deeper into whichever combinations interest them most. “We wanted to give people a quick taste of a lot of things in the first session so that they’d have several days to learn more about what they found most interesting,” Ibrahim said. “Many of the presenters will stick around after the presentation, so they’ll be around to talk during breaks.”
“We hope the presentations will give the audience a sense of how many experimental immunotherapies are out there, how many pathways they operate on, and how investigators are choosing what treatments to use in combination with them,” Chen said.