Combining ADCs with Immuno Oncology 202009

Creative BioLabs is a contract research organization based in New York that specializes in antibody discovery, engineering, and biomanufacturing solutions. They discuss the limitations of immuno-oncology and the potential for synergistic combination therapies. Cancer cells can evade immune recognition through various mechanisms, such as the tumor microenvironment being immunosuppressive and tumor cells modifying immune modulatory molecules. Immunogenic cell death is a type of cell death that activates an immune response and has been induced by certain drugs like enferocyclines and platinum agents. Immunogenic cell death is characterized by the secretion of damage-associated molecular patterns. Certain cytotoxic compounds and radiation can induce immunogenic cell death and activate immune cells. Dendritic cells play a key role in antitumor immunity, and direct activation of these cells can help increase tumor-reactive T-cells and reduce immunosuppression. The delivery and release of ADC Welcome to Creative BioLabs, 100% of the effort, 100% of the service. As a dynamic contract research organization, we are based in New York and serve the whole world. Our seasoned scientists are skilled in antibody discovery, antibody engineering, and biomanufacturing solutions. Today, we will talk about some knowledge of ADC therapy combined with immuno-oncology agents with our scientist, Sonny. Hi, Sonny, could you tell us what is the main defect of immuno-oncology? Is there any way to solve this defect? Immuno-oncology has emerged as one of the most promising approaches to improve the therapeutic efficacy and durability of clinical responses in cancer patients. However, despite the clinical breakthroughs achieved with immunotherapies, like the checkpoint blockade, the overall proportion of patients experiencing durable responses to single-agent immunotherapy remains relatively small. Therefore, the real promise for most cancer patients does not lie in monotherapeutic approaches, but in synergistic combination therapies. It combines the best of immuno-oncology with the immune-promoting properties of other therapeutic modalities. The latter help to breach physical barriers, to overcome immune-suppressive networks within the tumor microenvironment, and improve immune cell infiltration into tumors. In short, synergistic combination therapies can well solve the main problems of immuno-oncology. How do cancer cells evade immune recognition? Well, first, the tumor microenvironment is often bathed in anti-inflammatory molecules, such as adenosine and TGF-beta, that limit the potency and activity of immune cells in the tumor tissue, as well as tumor proximal lymphatics, and allow tumors to grow in an uncontrolled manner. One thing worth mentioning is that, the tumor microenvironment is quite immunosuppressive, preventing the immune system from mounting a sufficient anti-tumor response. Second, tumor cells can modify surface expression of a number of immune modulatory molecules, to escape T cell recognition, and, dampen T cell effector function. Third, down-regulation of major histocompatibility complex I further limits T cell detection of tumor antigens. And increased programmed death ligand I expression, and the presence of other inhibitory immune checkpoints can mediate T cell, energy and exhaustion, thereby, neutralizing the immune response. What is the immunogenic cell death? Immunogenic cell death is a specific type of cell death, resulting in a regulated activation of the immune response. This cell death is characterized by aptotic morphology, maintaining membrane integrity. The hallmark outcome of immunogenic cell death in cancer therapy is the killing of cancer cells, that subsequently induces anti-cancer immunity, and formation of an immunological memory. What are the main inducers of immunogenic cell death? Which inducers can be used for tumor treatment? Classic immunogenic cell death inducers include enferocyclines, cardiac glycosides, and notable platinum agents. However, these drugs cannot be considered successful as ADC payloads, due to either an inability to chemically link them to an antibody, or a lack of sufficient potency. To overcome these limitations, next generation enferocycline containing ADCs with significantly higher potency and site-specific conjugation, have been recently developed. These next generation of ADCs have been shown to possess immunostimulatory properties, in preclinical models. Certain microtubule inhibitors, and DNA targeting agents were shown to be exceptionally potent payloads for ADCs. We have seen recent data provide striking evidence, that ADCs conjugated with these microtubule inhibitors, or DNA targeting agents provoke strong innate, and adaptive immune responses against syngeneic tumor models. Thereby, confer anti-tumor protection via direct effects on antigen-presenting cells, and by inducing immunogenic cell death. In addition, these agents exhibit profound anti-tumor synergy with immuno-oncology drugs, with different mechanisms of action. What are the characteristics of immunogenic cell death? Immunogenic cell death is characterized by secretion of damage-associated molecular patterns. There are three most important damage-associated molecular patterns, which are exposed to the cell surface during immunogenic cell death. Calreticulin is one of the damage-associated molecular pattern molecules, that is normally in the lumen of the endoplasmic reticulum. It is translocated after the induction of immunogenic death to the surface of dying cell, where it acts as an, eat-me signal for phagocytes. High-mobility group BOX1 is considered to be a marker of late immunogenic cell death, and its release to the extracellular space, seems to be required for the optimal presentation of antigens by dendritic cells. It binds to several pattern-recognition receptors, such as Toll-like receptors 2 and 4, which are expressed on APCs. ATP released during immunogenic cell death functions as a find-me signal for phagocytes, when secreted and induces their attraction to the site of immunogenic cell death. Also, binding of ATP to purinergic receptors on target cells has immunostimulatory effect, through inflammasome activation. What are the mechanisms of immune cell activation? Certain classes of cytotoxic compounds and radiation, have been shown to induce immunogenic cell death. It leads to potent stimulation of effector T-cell activation, as well as their recruitment into tumors. Well, the direct mechanism of immune cell activation, namely the maturation and activation of APCs, such as dendritic cells, has recently been attributed to certain microtubule-destabilizing ADC warheads. What do you think, are some effective inducers of functional dendritic cells maturation? Of all the agents tested, dolastatins and their synthetic orostatin analogs, as well as the matensinoids DM1 and ansamidicin P3, a precursor in the synthesis of DM1, are by far the most potent inducers of functional dendritic cells maturation. From the perspective of immunotherapy, what are the advantages of direct activation of antigen-presenting cells? I think the direct activation of antigen-presenting cells, such as dendritic cells, is highly attractive and may provide a fertile ground for the induction of potent antitumor immunity. Dendritic cells are central players during the initiation of antitumor immunity, once they are fully matured. The vast majority of dendritic cells found in solid tumors are dysfunctional immature dendritic cells, that are tolerogenic and contribute to the immunosuppressive tumor microenvironment. Any therapeutic approach, which matures and converts these cells into professional EPCs, will not only help to increase recruitment of tumor-reactive T-cells, but will also significantly reduce immunosuppression at the tumor site. What are the characteristics of ADC delivery to tumors and payload release? Delivery of ADCs to tumors and release of the payload may follow completely different kinetics and be heavily dependent on the antibody selectivity, functionalization, as well as linker chemistry and payload characteristics like membrane permeability. In addition, cleavage of the payload from the linker may result in altered payload metabolite structures and properties like polarity, target engagement, and membrane permeability. What is brontoxamabvidotin, what does it do, and how does it work? Brontoxamabvidotin is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma, and systemic anaplastic large-cell lymphoma. Brontoxamabvidotin has been reported to not only induce sustainable therapeutic responses in heavily pretreated cancer patients, but also to modulate the immune contexture and activation status, both in the periphery, and at the tumor site. Brontoxamabvidotin counteracts immunosuppression through cytokine upregulation, reduction of regulatory T-cells, as well as immune cell recruitment and activation. In the latter case, a lymphoma-specific increase in CD161-expressing T-cells, an increase in activation marker-positive T-cells, as well as DCs and B-cells expressing elevated levels of co-stimulatory molecules, have been observed in the blood of Brontoxamab-treated patients. What's more, a treatment-induced increase in tumor-infiltrating CD4 and CD8-positive T-cells was also observed. These ADC-based immune activation data are further substantiated by the analysis of serial biopsies taken from treatment-naive breast cancer patients. What are the advantages of combination therapy? The antitumor immunity mediated by ADCs indicates that there is a profound potential for synergies with immunooncology drugs. Recent publications demonstrated enhanced antitumor activity when TDM1 was combined with checkpoint inhibitors targeting CTLA4 and PD1. Related model research showed that ADCs armed with tubulin-depolymerizing warheads not only promote T-cell immunity on their own, but display greatly enhanced therapeutic efficacy when combined with immune checkpoint inhibition. The combination therapy resulted in almost universally complete responses in tumor-bearing mice. In addition, the combination therapy endowed the cured mice with a protective and long-lasting immunological memory, making them resistant to a re-challenge with tumor cells of the same origin. What types of ADC payload have entered the clinic? The ones entered the clinics are matensinoids, PBDs, and tubulicins. A matensinoid is a chemical derivative of matensine. Anticancer properties of matensinoids have been attributed to their ability to disrupt microtubule function. The matensinoid amtansine, for example, binds at the ends of microtubules, and thereby suppresses their dynamic instability. PBDs are derivatives of naturally occurring antibiotics that bind to the minor groove of DNA, forming inter- and intrastrand crosslinked adducts. Tubulicins are antimyotic agents that function to depolymerize microtubules. The preclinical data suggest that each ADC payload may have different effects on the immune microenvironment, and these effects may also be tumor-dependent. It will be important in the future to identify tumor biomarkers that may indicate sensitivity to ADC immunomodulation. And tumor biomarkers may identify tumor types, in which to combine ADCs with immunotherapy in turn. How does ADC regulate immune function? Preclinical data prove that ADC combined with orostatin, matensinoid, PBD, and tubulolisin payload has significant immunomodulatory effects. In addition, ADCs can directly activate DCs, leading to greater recruitment to and activation of CTLs within tumors. They can also induce immunogenic cell death of tumor cells, leading to an enhanced immune response. How to best administer ADC and immunooncology combinatorial therapies? We could hypothesize that cancer treatment using ADCs should be conducted first, or perhaps concomitantly with immunooncology therapy, such that the ADC can effectively begin to induce immunogenic cell death of the tumor cells, and stimulate antigen presentation, while simultaneous or subsequent immunooncology therapy works to enhance and sustain the immune response to the treated tumor. Alternatively, and depending on the ADC warhead, as well as the MOA of the immunooncology therapy, the latter may be administered first to trigger antitumor immunity. The ADC can then be administered to eliciting immunogenic cell death of the dying tumor cells, and to further promote DC maturation, thereby providing additional stimulatory signals to the already activated immune system. Such decisions on timing will depend on many factors, including the immunomodulatory effects of the ADC warhead, the mechanism of action of the immunooncology agent, and the immunological status of the tumor itself at the time of treatment. Clearly, more preclinical work needs to be done, and more clinical data need to be collected, to determine the proper sequence of ADC or immunooncology administration for a particular warhead, immunooncology therapy, and cancer type. With the current development progress in technology, will there be strategies to make the immune system better participate? With advances in antibody engineering and site-specific conjugation chemistries currently being applied to ADCs, it may be possible to load an antibody with multiple payloads all within one targeted therapeutic, in order to most efficiently induce immunogenic cell death. As such, modifying ADCs to deliver payloads that complement each other by eliciting immunogenic cell death, and or direct immune stimulation, may be a viable strategy to optimally engage the immune system. What is the difficulty in the dosage of ADC and immunooncology combinations? It is known that both ADCs and immunooncology agents can have significant and potentially fatal toxicities, associated with their administration in some cases. Lower drug doses than those used currently in single-agent regimens, may be administered to decrease the toxicities, associated with these drugs as individual therapies. The specific appropriate dose needs to be determined through a large number of experiments.