Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

Mass calibration of DES Year-3 clusters via SPT-3G CMB cluster lensing

We measure the stacked lensing signal in the direction of galaxy clusters in the Dark Energy Survey Year 3 (DES Y3) redMaPPer sample, using cosmic microwave background (CMB) temperature data from SPT-3G, the third-generation CMB camera on the South Pole Telescope (SPT). Here, we estimate the lensing signal using temperature maps constructed from the initial 2 years of data from the SPT-3G 'Main' survey, covering 1500 deg2 of the Southern sky. We then use this lensing signal as a proxy for the mean cluster mass of the DES sample. The thermal Sunyaev-Zel'dovich (tSZ) signal, which can contaminate the lensing signal if not addressed, is isolated and removed from the data before obtaining the mass measurement. In this work, we employ three versions of the redMaPPer catalogue: a Flux-Limited sample containing 8865 clusters, a Volume-Limited sample with 5391 clusters, and a Volume&Redshift-Limited sample with 4450 clusters. For the three samples, we detect the CMB lensing signal at a significance of 12.4σ, 10.5σ and 10.2σ and find the mean cluster masses to be M 200m = 1.66±0.13 [stat.]± 0.03 [sys.], 1.97±0.18 [stat.]± 0.05 [sys.], and 2.11±0.20 [stat.]± 0.05 [sys.]×1014 M⊙, respectively. This is a factor of ∼ 2 improvement relative to the precision of measurements with previous generations of SPT surveys and the most constraining cluster mass measurements using CMB cluster lensing to date. Overall, we find no significant tensions between our results and masses given by redMaPPer mass-richness scaling relations of previous works, which were calibrated using CMB cluster lensing, optical weak lensing, and velocity dispersion measurements from various combinations of DES, SDSS and Planck data. We then divide our sample into 3 redshift and 3 richness bins, finding no significant discrepancies with optical weak-lensing calibrated masses in these bins. We forecast a 5.7% constraint on the mean cluster mass of the DES Y3 sample with the complete SPT-3G surveys when using both temperature and polarization data and including an additional ∼ 1400 deg2 of observations from the 'Extended' SPT-3G survey

Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV⁺ Cancers.

Cancers induced by human papillomaviruses (HPV) should be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7. However, advanced forms of cervical cancer, driven by HPV, are poorly responsive to immune response-enhancing treatments involving therapeutic vaccination against these viral neoantigens. Leveraging a transgenic mouse model of HPV-derived cancers, K14HPV16/H2b, we demonstrated that a potent nanoparticle-based E7 vaccine, but not a conventional "liquid" vaccine, induced E7 tumor antigen-specific CD8 <sup>+</sup> T cells in cervical tumor-bearing mice. Vaccination alone or in combination with anti-PD-1/anti-CTLA4 did not elicit tumor regression nor increase CD8 <sup>+</sup> T cells in the tumor microenvironment (TME), suggesting the presence of immune-suppressive barriers. Patients with cervical cancer have poor dendritic cell functions, have weak cytotoxic lymphocyte responses, and demonstrate an accumulation of myeloid cells in the periphery. Here, we illustrated that myeloid cells in K14HPV16/H2b mice possess potent immunosuppressive activity toward antigen-presenting cells and CD8 <sup>+</sup> T cells, dampening antitumor immunity. These immune-inhibitory effects inhibited synergistic effects of combining our oncoprotein vaccine with immune checkpoint-blocking antibodies. Our data highlighted a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of myeloid cells on CD8 <sup>+</sup> T-cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPV <sup>+</sup> cancer-induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious antitumor immune responses

Modeling and in vitro experimental validation for kinetics of the colonoscope in colonoscopy

Colonoscopy is the most sensitive and specific means for detection of colon cancers and polyps. To make colonoscopy more effective several problems must be overcome including: pain associated with the procedure, the risk of perforation, and incomplete intubation colonoscopy. Technically, these problems are the result of loop formation during colonoscopy. Although, several solutions such as modifying the stiffness of the colonoscope, using an overtube and developing image-guided instruments have been introduced to resolve the looping problem, the results of these systems are not completely satisfactory. A new paradigm to overcome loop formation is proposed that is doctor-assistive colonoscopy. In this approach, the endoscopists performance is enhanced by providing using a kinetic model that provides information such as the shape of the scope, direction of the colon and forces exerted within certain sections. It is expected that with the help of this model, the endoscopist would be able to adjust the manipulation to avoid loop formation. In the present studies, the kinetic model is developed and validated using an ex vivo colonoscopy test-bed with a comprehensive kinematic and kinetic data collection. The model utilizes an established colon model based on animal tissue with position tracking sensors, contact force sensors for the intraluminal portion of the scope and a Colonoscopy Force Monitor for the external insertion tube

Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

B and T lymphocyte attenuator mediates inhibition of tumor-reactive CD8+ T cells in patients after allogeneic stem cell transplantation.

Allogeneic stem cell transplantation (allo-SCT) can cure hematological malignancies by inducing alloreactive T cell responses targeting minor histocompatibility antigens (MiHA) expressed on malignant cells. Despite induction of robust MiHA-specific T cell responses and long-term persistence of alloreactive memory T cells specific for the tumor, often these T cells fail to respond efficiently to tumor relapse. Previously, we demonstrated the involvement of the coinhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8(+) T cell immunity. In this study, we investigated whether B and T lymphocyte attenuator (BTLA) plays a similar role in functional impairment of MiHA-specific T cells after allo-SCT. In addition to PD-1, we observed higher BTLA expression on MiHA-specific CD8(+) T cells compared with that of the total population of CD8(+) effector-memory T cells. In addition, BTLA's ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by myeloid leukemia, B cell lymphoma, and multiple myeloma cells. Interference with the BTLA-HVEM pathway, using a BTLA blocking Ab, augmented proliferation of BTLA(+)PD-1(+) MiHA-specific CD8(+) T cells by HVEM-expressing dendritic cells. Notably, we demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8(+) T cells in respectively 7 and 9 of 11 allo-SCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Furthermore, these expanded MiHA-specific CD8(+) T cells competently produced effector cytokines and degranulated upon Ag reencounter. Together, these results demonstrate that BTLA-HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation therapies