The foundations of cancer immunotherapy date back to the late 1800s, when rare cancer remissions or regressions were reported to have occurred in patients who had developed a bacterial skin infection called erysipelas. Immunotherapy in the broader sense can be traced even further back in history. Nevertheless, the use of the immune system as a therapeutic strategy underwent its most extensive transformation only in recent decades.

Currently, immunotherapies are being developed in several clinical areas including autoimmune conditions, inflammatory diseases, and transplantation. However, immunotherapies are still mostly about cancer, where the need for life-extending therapies seems to be especially pressing. In this article, we will emphasize how immunotherapies against malignancies are improving thanks to immune system insights, cancer biology advances, and new technologies.

Harnessing the qualities of red blood cells

“We have known for about a century that red blood cells can be easily transfused between people, and this knowledge has been critical for our work,” says Pablo J. Cagnoni, MD, CEO of Rubius Therapeutics. The unique properties of red blood cell progenitors are the basis of an effort at Rubius that contributed to the development of the Rubius Erythrocyte Design (RED) Platform. This proprietary technology converts very early progenitor cells into red blood cells and engineers them into cellular therapies called Red Cell Therapeutics (RCTs). The RED Platform is now being used to develop therapeutics for cancer and autoimmune diseases.

Rubius’ first product to enter clinical trials is RTX-240, a broad stimulator of the immune system. RTX-240 can activate and expand T cells and natural killer cells and is currently being examined in patients with relapsed/refractory or locally advanced solid tumors and relapsed/refractory acute myeloid leukemia.

Rubius Therapeutics is developing RTX-240, an allogeneic, off-the-shelf Red Cell Therapeutic that can stimulate adaptive and innate immunity by activating and expanding natural killer cells and T cells to generate an antitumor response. The company cites the potential for enhanced efficacy and safety by confining RTX-240 to the vasculature. At present, RTX-240 is being examined in patients with relapsed/refractory or locally advanced solid tumors and relapsed/refractory acute myeloid leukemia.

“The second side of our platform is what we call antigen-specific immune stimulation,” Cagnoni continues. This therapeutic modality involves the engineering of allogeneic artificial antigen-presenting cells to direct T cells to produce cytokines and engage in cytolytic activities.

“As part of this program, we will start testing RTX-321 in patients very soon,” Cagnoni notes. RTX-321, engineered to express a human papillomavirus peptide antigen, a co-stimulatory signal, and a cytokine, mimics the interaction between human T cells and antigen-presenting cells and induces a tumor-specific immune response by expanding antigen-specific T cells.

An additional avenue that scientists at Rubius are pursuing is the use of RCTs for the treatment of autoimmune diseases. “By providing a key antigen on the surface of red blood cells, we can reset a patient’s immune system to keep it from attacking a particular organ,” Cagnoni asserts. Preclinical studies for type I diabetes as part of this research effort are currently ongoing at Rubius.

One of the limitations in developing immuno-oncology drugs, as compared to drugs in most other therapeutic areas, is that many fundamental differences exist between animals and humans in the organization and function of the immune system. “That challenge is not unique, but it is more complicated in immuno-oncology,” Cagnoni acknowledges. “It creates an added level of uncertainty when translating preclinical discoveries into clinical developments.”

Immunotherapies for refractory and difficult-to-treat cancers

“If we could understand why some people reengage their immune system after receiving chemotherapy, while others don’t, we could think about how to combine various therapeutic modalities and in what sequence,” says Christian Rohlff, PhD, CEO of Oxford BioTherapeutics. The company is focusing on using proprietary immuno-oncology technology and antibody-drug conjugates to develop novel therapeutics that can reengage the immune system to destroy cancer cells.

Advances in recent years catalyzed the emergence of powerful immuno-oncology tools that include immunotherapies, bispecific antibodies, cell therapies, antibody-drug conjugates, and cancer vaccines. A key product in the Oxford BioTherapeutics pipeline, OBT076 (MEN1309), is a fully human immunoglobulin G1 antibody drug conjugate that targets CD205, an endocytic receptor highly expressed in lymphomas and leukemias and on the surface of many solid malignancies. CD205 expression on cancer cells also correlates with poor survival.

“This may appear counterintuitive because CD205 is also an immune receptor found on certain immune cells that are immune stimulatory,” explains Rohlff. CD205 exists on B and T lymphocytes, on certain dendritic cell subsets, and on macrophages, and it participates in antigen uptake, processing, and presentation. Preclinical and translational data at Oxford BioTherapeutics provided the proof of concept that OBT076 achieves antitumor activity in vitro and in animal models of patient xenografts.

Currently, OBT076 is being evaluated in a Phase I clinical trial in patients with CD205-positive solid tumors. Targeting CD205-expressing cells not only removes cancer cells but also allows the immune system to reset and restart in an immunogenic direction. If this strategy succeeds, Rohlff suggests, it will “open opportunities to provide better patient outcomes, particularly for refractory and difficult-to-treat cancers.”

The adenosine-ATP pathway in immuno-oncology

“In the immuno-oncology world, we look for instances where the tumor has ‘hijacked’ immune-related biology to acquire some sort of survival advantage,” says Terry Rosen, PhD, CEO of Arcus Biosciences. A major part of the clinical oncology work at Arcus has involved the identification of molecules that modulate the ATP-adenosine pathway, which plays a critical role in modulating the immune response in health and disease.

Historically, ATP has mostly been associated with energy homeostasis. “ATP,” Rosen notes, “also has an important role from an immunology standpoint.”

The levels of ATP and its degradation product, adenosine, are very low in the extracellular fluid. After cellular lysis, the high ATP concentrations in the blood serve as a danger signal to the immune system, which instigates an inflammatory response.

The signal also engages a feedback mechanism in which extracellular ATP is progressively dephosphorylated by two enzymes, CD39 and CD73. CD39 cleaves the first two phosphates, and CD73, the rate-limiting enzyme, cleaves the third phosphate to generate adenosine. These two enzymes are highly expressed on cells in the tumor microenvironment.

“This confers a survival advantage to the tumor,” Rosen explains. Adenosine binds to adenosine 2 receptors on immune cells and causes them to become quiescent. From a therapeutic standpoint, this provides opportunities to either block the formation of adenosine by enzymatic inhibition, or to block the action of adenosine using receptor antagonists.

Arcus scientists recently disclosed data on the use of AB680, the first small-molecule CD73 inhibitor in the clinic, in patients with metastatic pancreatic cancer. Pancreatic cancer emerged as an ideal setting to study this molecule due to the high medical need in this condition, the current lack of effective therapies, the importance of CD73 and adenosine, and the lack of contribution/clinical benefit of anti-PD1 therapies when combined alone with the current standard-of-care treatment.

“In a dose-escalation study in healthy volunteers, early data not only confirmed the safety and outstanding pharmacodynamic properties of AB680, but it also provided encouraging signs with respect to clinical activity,” Rosen asserts. The response rate with AB680 combined with the current standard of care (gemcitabine plus abraxane) and zimberelimab (Arcus’s PD-1 antibody) was slightly over 40% in this initial study group, as compared to 25%, which is the historical response rate with gemcitabine and abraxane.

Arcus recently opened the expansion phase of this study and will be adding a control arm shortly. “We hope to share some of the randomized data later this year,” Rosen adds.

Another molecule in the Arcus pipeline, AB928, blocks the receptors that are important for adenosine action. AB928 is the first molecule to enter the clinic that inhibits both the 2A and 2B adenosine receptors. “Although both receptor types are important for the immune response, the 2B receptor is additionally often found on tumors,” Rosen notes. “The 2B receptor’s activation by adenosine favors tumor survival, because this activation can drive several oncogenic pathways.”

An important strategy at Arcus relies on pursuing combination therapies for oncology applications. “We try to focus on targets where the drugs can be combined with other therapies as well as with each other,” Rosen states. “That is where we see a real advantage.”

In the ARC-7 Phase II, randomized, open-label clinical trial for PD-L1-high non-small cell lung cancer, the triple combination of anti-TIGIT antibody, anti-PD1 antibody, and AB928 is being compared to the dual anti-PD1 and anti-TIGIT combination and with anti-PD1 therapy alone. “Because CD73 and adenosine are important in front-line treatments for non-small cell lung cancer,” Rosen explains, “we think that the AB928 arm provides a real opportunity for differentiation.”

CD73 is the primary enzymatic producer of immunosuppressive adenosine in the tumor microenvironment, and high CD73 expression is associated with significantly poorer prognosis in several tumor types. To effectively eliminate CD73-derived adenosine, Arcus Biosciences has developed AB680, a potent and selective small-molecule inhibitor of CD73.

One benefit of this particular trial design is that if a patient in the anti-PD1 arm of this trial progresses, indicating unfavorable prognosis, they can also then receive the triplet regimen, where they may see a benefit should CD73 be important for progression. “Immuno-oncology has already transformed the prognosis for patients,” Rosen declares. “We have opportunities to advance immuno-oncology even further with unique molecules.”

Targeting the unique “pocketome” of cancer cells

“In our proof-of-concept study, we showed that chemically programmable and switchable chimeric antigen receptor (CAR) T cells can kill folate receptor–expressing cancer cells,” says Christoph Rader, PhD, professor and associate dean at the Skaggs Graduate School of Chemical and Biological Sciences of Scripps Research.

In much of his research, Rader explores the interface between using chemistry and biology to develop antibody therapeutics. “The general view about cancer cells is that what is on the cell is primarily an antibody target, and that what is in the cell is primarily a small-molecule target,” Rader states. However, structural biology approaches have revealed that valuable pockets for small molecules also exist on the surface of cancer cells.

One example is the folate receptor, a natural pocket that binds folate with nanomolar affinity. “There are many other pockets for which it is possible to develop small molecules that are not endogenous to cells but come from actual or virtual chemical libraries,” Rader observes.

Scientists in Rader’s group became interested in designing molecules that can recognize the surface of malignant cells not through antibody recognition but through small-molecule recognition. “These molecules target this pocketome, which is a fraction of the surfaceome, by recognizing pockets that can be quite distinctive for cancer cells as compared to normal cells,” Rader explains. This effort led to the development of a platform that uses a chemically programmable antibody fragment as an on/off switch to recruit and activate CAR T cells to target the folate-binding site of the folate receptor.

“We call these cells chemically programmable CAR T cells,” Rader notes. The folate receptor is overexpressed on malignant cells, which extensively rely on folate for nucleic acid synthesis. Using this platform and in vitro and mouse models of human ovarian cancer, Rader and colleagues have investigated the possibility of eradicating folate-receptor-expressing malignant cells.

“Going forward, we are interested in broadening this approach for small molecules that originate from chemical libraries,” Rader declares. This would allow scientists to expand their study of the cancer cell surface targetome and to reach pockets that cannot be accessed or distinguished by antibodies.

“The proof of concept is there,” Rader asserts. “What is missing is the demonstration that this strategy can be broadly applied to synthetic small molecules emerging from libraries.” Structural biology efforts to map these pockets and develop targeting molecules against every protein of the genome are critical for these efforts. “I would like to see structural biology–enabled small-molecule discovery move faster and provide molecules that other investigators could test using our system,” Rader says.

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