Although great strides have been made towards developing safer and more effective treatments for cancers of all types in the past few decades, the fact remains, some forms of this complex disease are exponentially more challenging to treat than others. Namely, those involving hematological malignancies have long evaded any form of effective treatment that does not carry with it significant costs to the patient’s general health and well-being. Even now, as mortality rates steadily decline and prognoses continuously improve, cancers such as leukemia and lymphoma remain extremely serious and often fatal in large part due to a lack of treatment options capable of addressing these complex malignancies without a considerable amount of collateral damage left in their wake.
With the unique ability to specifically target cancer cells while leaving healthy tissues untouched, CAR T-cell therapy is a relatively new treatment lauded by many as the usher of oncology's next generation treatment with targeted efficacy and reduced side effects. But how does this pioneering treatment's efficacy stack up against different types of cancer?
Efficacy by Type
While CAR T-cell therapy has been demonstrated effective against a multitude of cancer types, it is actually more effective against hematological malignancies than it is against solid-state tumors. CAR T-cells circulating within the bloodstream are easily able to access and eliminate hematological malignancies. In contrast, solid-state tumors develop from cells embedded within living tissues, due to trafficking and infiltration issues, are far more difficult for CAR T-cells to penetrate effectively.
Beyond trafficking and infiltration, however, there are also a number of problems arising not from the mechanism of treatment but from the nature of solid-state tumors themselves. Because these types of malignancies generally carry with them additional cell types that support tumor growth, such as Tregs, TAMs, and MDSCs, solid tumors often create hostile microenvironments that inhibit the function of CAR T-cells.
Meanwhile, solid tumors are rarely consistent with the exact same type of cancerous cells throughout; instead, they are often heterogeneous, containing cells that vary in both their antigen expressions and responses to treatment. This creates recognition issues for the CAR T-cells. This is in sharp contrast to hematological malignancies, which are commonly homogenous in their expressions and are easily targeted via their specific antigen. Additionally, the toxicity associated with CAR T-cell therapy has a much higher instance in the case of solid-state tumors, with significantly increased potential for off-target effects and unnecessary damage to the healthy tissues surrounding these tumors. Thus, CAR T-cell therapy is currently better suited to treating systemic cancer types than those occurring at a single site.
Innovation for Improved Performance in Solid Tumors
Despite these impediments, CAR T-cell continues to hold a significant amount of potential for advancing the treatment of solid-tumor malignancies, with researchers currently deploying a number of strategies to improve its performance in this area as well as devising new methods of implementation that may support and enhance existing treatments.
One such strategy entails enhancing recognition by training CAR T-cells to express more than one type of CAR receptor, i.e., recognize more than one type of antigen, to combat heterogeneous cancer cells. In another approach, trafficking, and infiltration is improved by adjusting the chemokines, engineering the CAR T-cells to express chemokine-specific receptors. An additional method focuses on improving the CAR T-cell's ability to infiltrate solid-state tumors and withstand their hostile microenvironments by increasing the expression of potassium, which boosts the performance of T-cells function, as well as deploying suppressor antibodies in tandem with genetic manipulation to defeat the cells that support tumor growth, Tregs and MDSCs.
Finally, researchers are also exploring alternative delivery methods that allow CAR T-cells to target solid-state tumors in a more precise and regional manner. These include performing regional intraventricular delivery within the tumor location to allow for more specific targeting as well as combining CAR T-cell therapy with surgical treatment, with T-cells being applied directly to the afflicted site (surgical margins) after the tumor has been removed, eliminating any remaining cancerous cells and thus preventing relapse. The latter method has already shown great promise in early trials; in one Penn Medicine study, mice were treated with a special fibrin gel containing human CAR T-cells following partial tumor removal, residual cancer cells were found to be eliminated entirely in nineteen of twenty cases.
In our next installment of the MIDI Innovation Vault™, we will begin to focus on how the CAR T-cell production and treatment cycle is based on a Centralized Manufacturing approach and how there is a phase shift needed into a Regionalized Point-of-Care approach, with production at or near the patient treatment site. This will facilitate therapy democratization, allowing more people to both access and afford the treatment. Changes to current logistics, infrastructure and production process need to be implemented and will be discussed.
