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Destruction of a cancer cell, computer illustration.
Solid tumors are notoriously difficult to suppress. They survive and thrive in the body despite all efforts to keep them under control – and even resist the latest immunotherapies such as PD-1 and PD-L1 that target checkpoint inhibitors. One of the ways researchers are trying to tackle this problem is by disarming the tumor’s defenses against the immune system. This paper describes one such effort: a novel antibody that could reinvigorate antitumor responses in patients with treatment-resistant tumors.
Tumor checkpoint targeting
Patients with solid tumors may be offered a treatment called checkpoint inhibitors. This class of cancer drugs uses antibodies to release the immune system’s inherent ability to fight cancer. The antibodies block inhibitory proteins called immune checkpoints, which are found on the surface of specific immune cells and cancer cells. This interaction re-stimulates T cells, allowing them to recognize and attack cancer cells more effectively.
A major problem with these medications is resistance. In these cases, checkpoint inhibitors may never provoke a response in the patient. Alternatively, treatment may prove beneficial initially but become less effective over time. This may occur due to changes in the tumor environment, an upregulation of various tumor checkpoint proteins, and other factors. Developing strategies to overcome resistance will be critical to unlocking the full potential of checkpoint inhibitors and improving outcomes for patients battling solid tumors.
How the experimental antibody works
Researchers at the Vall d’Hebron Institute of Oncology in Spain have developed an antibody that could offer renewed hope to people who have undergone more than one failed cancer treatment. Early clinical results show that their FS222 antibody can disarm tumors even when other anti-cancer options fail.
This antibody functions markedly differently than the antibodies found in checkpoint inhibitors. Inhibitors bind exclusively to checkpoint proteins, such as PD-1 found mainly on white T cells, or PD-L1, its binding partner on tumor cells. The interaction blocks the interaction of other proteins with the inhibitory checkpoint.
In contrast, the experimental antibody is bispecific; it binds to proteins on tumor cells and on T cells. More specifically, it binds tightly to PD-L1 checkpoint proteins on one side and to a costimulatory receptor on T cells on the other. This antibody prevents checkpoint protein interactions and encourages the T cell to activate tumors and retaliate through the T cell’s costimulatory receptors.
Selectively activating the immune system against tumors in this way could provide particular benefits for patients who have failed anti-PD-1 blockade therapy. The treatment could deliver a double whammy by simultaneously targeting a PD-1 partner molecule and riling up T cells.
The highly specific binding also ensures that costimulatory receptor activation occurs primarily in the tumor microenvironment where PD-L1 checkpoints are expressed. This should reduce the risk of systemic immune activation and possible adverse effects.
Figure 1: Experimental antibody mechanism. The antibody contains a total of four binding sites: two bind … [+]
The safety of antibodies is acceptable
The primary goal of the trial was to determine the safety and dosage of the experimental antibody. More than 100 patients with various advanced solid tumors participated in the study, including melanoma, non-small cell lung cancer, ovarian cancer, triple-negative breast cancer and colon cancer. All participants had previously undergone at least one cancer treatment that was unsuccessful.
The patients received increasing doses of the experimental antibody every three to four weeks. Treatment was stopped if the patient’s condition worsened (for example, if the tumor increased in size or spread) or if the antibody caused unacceptable toxicity. These early results reflect results from only 90 patients; they were exposed to the antibody for an average of 82.5 days.
Overall, the antibody showed an acceptable and manageable safety profile. Patients often reported fever and a general lack of energy and strength. The treatment also increased liver enzymes and decreased the number of platelets and neutrophils, a type of white blood cell.
Five patients experienced febrile neutropeniaa serious condition characterized by fever, an abnormally low neutrophil count, and a high risk of infection. Other less common but dangerous symptoms include fever and cytokine release syndrome, an inflammatory condition often caused by certain immune therapies, such as CAR T therapy.
Promising antitumor results for melanoma
In addition to its safety profile, the antibody also illustrated encouraging antitumor responses. The treatment achieved an overall response rate of almost 16% across all tumor types in the study, including ovarian, colon and breast cancer. However, the antibody caused the most significant responses in patients with advanced melanoma.
Cutaneous melanoma is a common and aggressive skin cancer that starts in pigment-producing cells. Anti-PD-1 checkpoint inhibitors are a viable treatment option for people with advanced and spreading forms of this cancer, but the tumor can return. In the study, the experimental antibody induced responses in 60% of these patients who had previously tried PD-1 checkpoint inhibitors – a marked increase compared to the other tumor types. In addition, the cancer was controlled in more than 85% of this cohort. These results provide an optimistic future for patients who have experienced a relapse after trying checkpoint inhibitors.
Looking forward
Solid tumors are resistant to many cancer treatments and can render them ineffective, as is the case with checkpoint inhibitors. The experimental antibody used in this study offers a new solution for people whose cancer has relapsed after treatment, with particular benefit for patients with advanced melanoma. It will be exciting to see how the study continues to evaluate the efficacy of the therapy in a larger participant population.
This article joins a growing series on monocancer treatments, including new immunotherapies such as CAR T therapy And checkpoint inhibitors. Find more at www.williamhaseltine.com.