Following from last year’s record year of attendance held in Boston, this year’s 38th annual Society for Immunotherapy of Cancer (SITC) meeting held in sunny San Diego proved just as popular attracting a global audience including basic and clinical investigators from academic institutions, industry, regulatory agencies, as well as pharmacists and payers, who wished to learn more about cancer immunology and immunotherapy and its incorporation into current (and future) effective cancer treatments.
Today, we have a better understanding of cancer immunobiology leading to the successful development of novel immune-based treatment options to improve cancer patient outcomes. Unfortunately, only around 20 to 30 percent of solid cancer patients given immunotherapies go into long-term remission. The goal at SITC therefore “aims to make cancer immunotherapy a standard of care and the word “cure” a reality for cancer patients everywhere” with this year’s focus to “advance the science, discover breakthroughs, and educate the world on cancer immunotherapy. The 3-day meeting and pre-meeting workshops available offered valuable scientific educational sessions with key opinion leaders and the latest cutting-edge research summarized in talks and over 1500 posters.
While dedicated sessions and poster presentations addressed the complexity of the immune network and tumor microenvironment using various high-dimensional assays for an exploration of both tissue and blood samples at the genomic, transcriptomic, proteomic, and even microbiome level, from my perspective several main themes transpired that included: 1. The integration of spatial biology techniques in clinical trials; 2. The importance of neutrophils and 3. Novel drug engineering strategies with the rise of antibody-drug conjugates (ADCs) and improved Chimeric Antigen Receptor (CAR) designs.
In a packed room, Genentech highlighted their recent data from the now completed IMpower 110 trial, with a talk entitled, “Tertiary lymphoid structures (TLS) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with first-line atezolizumab” https://jitc.bmj.com/content/11/Suppl_1/A690 with the over-arching theme to evaluate the clinical utility of TLS as a biomarker associated with clinical benefits from immunotherapy in patients with untreated metastatic non-small cell lung cancer (mNSCLC). Prior studies derived from expression analysis and spatial multiplexing techniques had indicated, that B-cell and plasma-cell gene expression signatures, as well as the presence of TLS are associated with improved overall survival outcomes in patients with mNSCLC treated with atezolizumab in the second line setting. The presented study analyzed patient baseline samples from IMpower110 and a Phase III study of first line atezolizumab vs chemotherapy in PD-L1-selected mNSCLC. Images of baseline samples in patients were reviewed for the presence of dense lymphoid aggregates with at least one distinct germinal center (TLS), lymphoid aggregates without any germinal centers (LA), or absence of both (neither). Of 422 patients in TLS biomarker-evaluable population, 62 samples were characterized as TLS, 151 as LA and 209 as neither. Importantly, the TLS subgroup showed improved progression free survival (PFS) and overall survival (OS) in the atezolizumab arm compared to the chemotherapy arm. The conclusion for this advanced study indicated that the presence of TLS in baseline tumor tissues may identify patients with mNSCLC who are most likely to benefit from first-line PD-(L)1 inhibitors, especially those with tumors with intermediate or low levels of PD-L1 expression.
Additional talks and posters addressing the presence and density of various immune cell types were high on the agenda. This is especially important as we can now start to appreciate that the spatial pattern analysis of tumors and specific cell co-localizations could provide detailed information on overall cancer prognosis, supporting the value of spatial measurement of specific immune cell infiltrates as novel, robust tumor-immune biomarkers. Much of the research on the response to immunotherapy has historically focused on adaptive immune cells such as T cells that are activated by immunotherapy and can learn to recognize and attack cancer cells. Recently however, innate immune cells such as neutrophils have received attention for their potential role in orchestrating immune evasion in cancer. Expanding on new data from their recently published Cell paper earlier this year1., researchers at Weill Cornell Medical and Graduate Schools, New York presented a talk entitled “T cell immunotherapies recruit and activate neutrophils to eliminate tumor antigen escape variants” https://jitc.bmj.com/content/11/Suppl_1/A979 and investigated how a T cell-based immunotherapy was able to destroy melanoma tumors (using a mouse model of melanoma development) even though many of the tumor cells lacked the markers or “antigens” targeted by the T cells. Data indicated that the T cells, in attacking the tumors, activated neutrophils which in turn killed the tumor cells that the T cells couldn’t eliminate. Additional studies from patients who had been treated with anti-OX40 (another checkpoint inhibitor) for head and neck cancers also exhibited similar results suggesting that contrary to popular belief, neutrophils can play a significant antitumor role, especially in escape mechanisms. Interestingly, my own poster entitled, “Spatial characterization of pro-inflammatory pathways in the pathogenesis of IBD-associated colorectal cancer” https://jitc.bmj.com/content/11/Suppl_1/A1646 using the Cancer Transcriptome Atlas (CTA) on the GeoMx® Digital Spatial Profiler (DSP, Nanostring Technologies) also alluded to the presence of neutrophils as an important component of the TME within primary tumors. Data highlighted that spatial resolution was essential in understanding not just cellular function, but linking biologically relevant interactions to specific cell types such as neutrophils, focusing on expression of specific chemokines and how they could participate in the formation, mobilization, and recruitment of neutrophils.
With over 200 posters encompassing keywords of CAR-T and ADCs, it’s clear that various antibody-redirected immunotherapeutic approaches devised to produce specific activity against cancer now are a promising therapeutic option. The fundamental components of an ADC include an antibody, a linker, and a payload. The choice and construction determine the clinical characteristics of the ADC, and one such design that aimed to improve therapeutic index while minimizing toxicity was the utility of immune-stimulating antibody conjugates. Data from a global group and led by Bolt Biotherapeutics showcased a “Phase 2 study of the HER2-targeting TLR7/8 immune stimulating antibody conjugate (ISAC) BDC-1001 monotherapy +/- nivolumab in patients with HER2+ colorectal, endometrial, or gastroesophageal cancer” https://jitc.bmj.com/content/11/Suppl_1/A811. Intratumoral delivery of antitumor antibodies and immunostimulatory adjuvants such as toll-like receptor (TLR)7/8 agonists has been shown to activate tumor resident antigen-presenting cells (APCs), driving uptake, processing, and presentation of tumor neoantigens to T cells that mediate antitumor immunity. The group had designed BDC-1001, a novel ISAC that consisted of an investigational biosimilar of the humanized monoclonal antibody trastuzumab chemically conjugated to a TLR7/8 agonist with a non-cleavable linker. BDC-1001 activated human myeloid APCs in addition to retaining antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). The group presented some results from their phase 2 (dose expansion) portion of the study to evaluate BDC-1001 alone and in combination with nivolumab, an immune checkpoint inhibitor targeting PD-1 in patients with HER2-expressing or HER2-amplified advanced/metastatic solid tumors, demonstrating the potential to address refractory and recurrent disease of HER2+ cancers.
SITC 2023 established that cancer immunotherapies are important in the treatment of cancer by demonstrating the dramatic increase in survival and quality of life for cancer patients. Nevertheless, since cancer is heterogenous and not one type of cancer, immunotherapy works for all. Depending on multiple factors, certain cancer immunotherapies work better for some cancer patients than others. The inclusion of multiple strategies and techniques, especially to elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes, will hopefully become a mainstay in clinical trial design.
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