Unlocking the potential of solid tumor immunotherapy

The rise of CAR T cell therapy

The first approval of a CAR T cell therapy was in 2017 and was considered a revolutionary moment in both the cell and gene therapy (CGT) and cancer treatment sectors. The first CAR T cell therapy was Kymriah from Novartis, for the treatment of pediatric and young adult acute lymphoblastic leukemia. This therapy is produced by isolating a patient’s own T cells (a type of immune cell) from their blood, modifying them so they present the cancer-fighting CARs (not to mention several other complex bioprocessing steps), then re-administering the CAR T cells back to the patient, intravenously.

Since Kymriah’s approval, a further five CAR T cell therapies have been approved by the FDA. These therapies have been able to achieve remarkable long-lasting remission and cures for diseases previously deemed incurable. An important thing to note about these, however, is that they have all been approved for treating blood cancers, rather than solid tumors.

Until recently, there were no immune cell therapies approved for treating solid tumors. The latest holy grail in the CGT industry has been reached by Iovance Biotherapeutics who, in February this year, became the first company to receive FDA approval for treating solid tumors with an immune cell therapy (called Amtagvi). The company’s initial indication is for people with advanced melanoma. However, they are currently testing their therapies for treating advanced lung, ovarian, head and neck cancers as well.

Given that 90% of all cancers are solid tumors, this was an exceptionally crucial milestone for the industry, but has proven to be a formidable challenge to achieve.

The challenges of treating solid tumors with immunotherapies

The inherent complexity in treating solid tumors arises from their distinct nature when compared to blood cancers, such as leukemia, which typically involve a singular cell type expressing uniform antigens. Solid tumors, on the other hand, present a daunting obstacle due to their heterogeneous composition of diverse cell types, each harboring different mutations and expressing a variety of antigens. This inherent variability poses a considerable hurdle in the development of biotechnological interventions for solid tumors. Additionally, the natural hostility of solid tumors towards T cells, often encapsulated by dense collagenous scar tissue, further complicates the therapeutic landscape.

Designing effective immune cell therapies or any therapeutic modality, becomes a more intricate task when dealing with these diverse tumors, demanding a sophisticated approach that can penetrate the tumor environment while targeting multiple antigens, concurrently. In essence, solid tumors exhibit a remarkable ability to evade our immune system, making the pursuit of effective treatments a notably intricate endeavor.

Another challenge associated with treating solid tumors with immunotherapies comes from the fact that these therapies are typically delivered intravenously. This means that the patient’s entire body will be exposed to the extra firepower the immune system has been armed with. This systemic biodistribution of these therapies often results in suboptimal doses, potential toxicities and limited efficacy of the treatment due to poor penetration into solid tumors.

This systemic delivery of immunotherapies can ultimately lead to systemic inflammation, which can be severely detrimental and often life-threatening. Our native immune system usually directs maximal efforts at the area identified as the site of infection or foreign body invasion. Hence, much of the focus for immunotherapy developers is now about not just being able to increase the firepower of our own immune systems, but to better direct them towards the true enemy and minimizing collateral damage elsewhere.

Optimizing immunotherapy for treating solid tumors

One way to achieve better accuracy in immunotherapies is through further advances in their biochemical design. For example, Iovance’s Amtagvi uses tumor-infiltrating lymphocytes (TILs) – the key difference here is that the T cells used are collected from the patient’s tumor, unlike CAR T cell therapies, where the T cells are collected from the patient’s blood. This technique has been shown to improve the therapy’s ability to target the solid tumors, compared with CAR T cell therapies. In addition to this specific technique, there are many other tumor-targeting compounds and designs currently under investigation by bioengineering researchers across this field.

Intratumoral injection

Another growing technique set to transform the efficacy of all immunotherapies, not just immune cell therapies, is the use of intratumoral injection. This involves administering the therapy directly into the tumor, ideally at multiple locations. This targeted approach presents a compelling solution to the limitations of the systemic administration described above. The strategy aims to enhance the in situ bioavailability of immunotherapies, potentially overcoming challenges related to systemic toxicities (such as inflammation and autoimmune reactions) and target under-occupancy within solid tumors.

The body’s immune responses are designed to act more effectively in a tissue-localized fashion. Intratumoral administration aligns with this native physiological principle. This targeted approach offers a feasible and effective delivery method in various organs, ensuring high initial concentration locally before gradual absorption into the bloodstream, potentially allowing for higher doses with better tolerability. It also enables the use of immunotherapies which can’t be delivered systemically because they cannot pass through from the vascular system into the tissue of the solid tumor, regardless of toxicity.

How to realize intratumoral therapy

Despite the potential benefits, challenges in the development of intratumoral therapy administration persist. Technical aspects, operator-dependent efficacy and the need for close monitoring are crucial considerations. For example, there are several surgical challenges associated with accessing highly variable and often sprawling tumors in hard-to-reach parts of the body, such as the brain, deep in the lungte or ovaries. There is also the physical challenge of injecting these shear-sensitive, viscous therapies without damaging them. Finally, there is also the challenge of optimizing drug retention and distribution within the tumor. This is a highly complex undertaking, requiring a multi-disciplinary approach during development.

Despite these challenges, innovative designs for localized drug delivery can significantly enhance the clinical efficacy of an immunotherapy, while mitigating potential safety concerns. The immunotherapy industry is currently seeing a shift in oncology practice, drug design and administration techniques, offering hope for improved outcomes for patients and reduced toxicity in the treatment of solid tumors.