Antibodies help create a safe passage for T cell troops to defeat solid tumours
Immunotherapies have been heralded as a revolutionary paradigm shift in how cancer is treated, thanks to the exceptional cancer-killing properties of checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Today, approved therapies Yescarta™ and Kymriah™, which use rewired T cells, have offered newfound hope for some patients with leukemia and lymphoma. In clinical trials, patients with these “liquid tumours” showed up to 94 percent remission rates after receiving CAR T therapies. This is especially impressive considering these patients had exhausted all other chemotherapeutic options, with no observable improvement.
The CAR T field continues to evolve expeditiously, with scientists leveraging advancements in synthetic biology, cell engineering, and gene editing technologies to foster extended clinical applications for these cell therapies. When it comes to tackling solid tumours effectively, however, the current generation of engineered immune cells falls terribly short, making this class of cancer a major unmet clinical need.
In a bid to understand just why CAR Ts are not able to eradicate cancer masses, researchers have examined the 3-dimensional structure and organization of tumours. By creating a map of a tumour’s complex tissue architecture and microenvironment, a clearer picture of the conditions and interactions encountered by CAR Ts on their cancer-killing missions has emerged.
A cancer immunology expert from the University of Basel, Dr. Abhishek Kashyap (pictured), has spearheaded a recent study published in the journal PNAS, using insights on the intricate tumour topology to design innovative therapeutic countermeasures. Together with co-first author Martina Schmittnaegel, he investigated whether chemically restructuring tumours could amplify the cancer-killing effects exerted by T cells.
Led by senior authors Alfred Zippelius and Michele De Palma, research teams from the University of Basel, École Polytechnique Fédérale de Lausanne and industry partner Roche used animal models of melanoma to validate their approach, generating encouraging preclinical results that point to a potential immunotherapeutic breakthrough.
“I am a cell biologist by training and have always been interested in dissecting the nature and dynamics of the tumour microenvironment,” says Kashyap. “The fact that cancer cells self-organize into these complicated structures, guided by signals from the extracellular matrix, has always intrigued me.”
On a microscopic level, the tumour resembles a city under siege: high walls line the periphery to evade recognition by circulating immune surveillance. Attempted takeovers by cytotoxic T cells are met with counterstrikes of immunosuppressive cytokine bombs, rendering these immune cells useless. In this hostile environment, even a barrage from battalions of supercharged CAR T cells has proven to be futile.
A key reason for this is that the blood vessels in and around the malignant mass tend to be leaky or stunted. Consequently, histological evidence shows that while CAR Ts are able to establish a beachhead around the outer fringes of the tumour, they have no means of penetrating deeper.
“Our hypothesis was that the killer T cells would only be able to invade and destroy the tumour if there are enough healthy blood vessels for them to penetrate.”
Tumours secrete chemical signals to cultivate a vascular network as a means of supplying oxygen and nutrients to the rapidly dividing cancer cells within, while removing waste metabolites. The degree to which this vascularization process (known as angiogenesis) occurs is closely linked to the propensity of the tumour to expand and metastasize. Contrary to expectation, however, therapies designed to arrest angiogenesis in tumours have not improved the long-term survival of cancer patients.
Kashyap and colleagues tested a divergent approach, repurposing these anti-angiogenic drugs for use in a different application. Besides blocking the formation of new capillaries, the hope was that anti-angiogenic antibodies would stabilize and restore the integrity of existing leaky vessels.
“Our hypothesis was that the killer T cells would only be able to invade and destroy the tumour if there are enough healthy blood vessels for them to penetrate,” he explains. Theoretically, this would provide a clear path of entry for CAR T cells towards the core of the tumour, allowing them to obliterate it from within.
Their strategy was to use a novel combination of three antibodies that have already been clinically adopted as cancer immunotherapies. One of them, a CD40 antibody, was selected for its ability to stimulate the immune system, unleashing potent anti-tumour T cell responses.
The other two represent anti-angiogenic antibodies. Bevacizumab, sold under the trade name Avastin, works by blocking a protein called vascular endothelial growth factor, while the third is in the process of clinical release. When used on their own, these immunotherapies did not improve patients’ prognosis as originally anticipated. The CD40 antibody’s performance was particularly dismal, with only 20 percent of cancer patients responding.
As a three-in-one cocktail, however, these coalition forces mobilized CD8+ cytotoxic T cells, and proved to have a striking synergistic effect in overcoming solid tumours.
“The most exciting moment for me was when I saw the degree of CD8+ T cell infiltration into the core of the tumour when we used our combinatorial antibody approach. By targeting the aberrant blood vessels, we were able to achieve incredible results that were not possible with the anti-CD40 monotherapy,” says Kashyap.
This work, a result of a collaboration between academic groups and an industry partner, Roche, blends immunotherapy, regenerative medicine and cell therapy principles to form a novel treatment algorithm.
Speaking on the obstacles associated with rolling this strategy out as a clinical intervention, Kashyap says “The appropriate selection of patient populations and choosing the right cancer indication could be challenging. This therapy may be beneficial for a specific niche of patients with non-responsive ‘cold’ tumours or tumours with a high angiogenic score.” The next steps for the lab involves using integrative, high-throughput multi-omics approaches to map how and why cancers acquire resistance to immune checkpoint therapies.
These exciting developments could spur a huge expansion of how currently approved CAR T-cell therapies are used, simply by deploying them in conjunction with other existing immunotherapies.
The article was originally published on the Centre for Commercialization of Regenerative Medicine’s (CCRM) Signals Blog on 20 Feb 2020: https://www.signalsblog.ca/antibodies-help-create-a-safe-passage-for-t-cell-troops-to-defeat-solid-tumours/
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