New therapy shows promise in strengthening CAR-T responses

Immunotherapy has emerged as one of the most promising approaches in the fight against cancer, with chimeric antigen receptor T-cell (CAR-T) therapy marking a significant breakthrough. However, the durability of CAR-T responses remains a major challenge, as many patients eventually relapse. One such promising approach is the development of NKTR-255, an investigational interleukin-15 (IL-15) receptor agonist. NKTR-255 has shown potential in boosting CAR-T therapies, particularly for patients with relapsed or refractory cancer, such as large B-cell lymphoma (LBCL).

Nektar Therapeutics, the developer of NKTR-255, has been at the forefront of advancing this promising therapeutic approach. Dr Jonathan Zalevsky, the company’s chief research & development officer, has played a pivotal role in driving the development of NKTR-255. With over 20 years of experience in the biopharmaceutical industry, particularly in oncology and immunology, Zalevsky’s work has helped shape the company’s approach to immune-oncology. In an interview with Drug Target Review, Zalevsky shares valuable insights into the mechanism of action of NKTR-255, its potential to transform cancer treatment, and its broader applications in combination therapies.

The need for better CAR-T therapies

CAR-T therapies have transformed the treatment landscape for cancer, offering the potential for long-lasting remission. However, despite the initial successes, many patients experience relapse within months of treatment. This is primarily due to the inability of the engineered CAR-T cells to persist long enough to maintain remission. The challenge, therefore, lies in enhancing the persistence and functionality of these cells.

IL-15 is a cytokine that plays a key role in the activation, survival and proliferation of key immune cells such as CD8+ T cells and natural killer (NK) cells. These immune cells are critical to the body’s ability to mount an effective anti-tumour response. However, the use of IL-15 in cancer therapy has been limited by its short half-life and limited ability to engage the full spectrum of immune responses. This is where NKTR-255 comes into play.

NKTR-255 is a novel long-acting IL-15 receptor agonist developed by Nektar to overcome the limitations of native IL-15. By stabilising the IL-15 molecule and prolonging its action, NKTR-255 can enhance CAR T-cell expansion and persistence. Unlike other IL-15 agonists, such as Anktiva (N-803) and Xencor’s RG2603, NKTR-255 retains the full spectrum of activity by engaging the interleukin-15 receptor alpha (IL-15Rα) and antigen-presenting cells. This results in a more holistic immune response, which not only boosts CAR T-cell numbers but also enhances their functionality, making them better equipped to target and destroy tumour cells.

Zalevsky explains that NKTR-255’s ability to increase the persistence of CAR-T cells is a key factor in its potential to improve the durability of CAR T-therapy responses. “NKTR-255 leads to re-expansion of CAR-T cells following treatment,” he notes.

In their trial, NKTR-255 effectively enhanced CAR T-cell kinetics, with the CD8+ CAR-T area under the curve (AUC) from 0-15 days post-administration, being 5.8 times greater than that of the placebo group. These findings suggest that NKTR-255 could significantly improve the effectiveness of CAR-T therapy in patients with relapsed or refractory cancers, potentially leading to longer-lasting responses and a higher likelihood of sustained remission.

Clinical success in large B-cell lymphoma

One of the most promising areas for NKTR-255 is its potential in combination with CAR-T therapy for patients with LBCL. In a clinical trial conducted by Nektar, patients who received NKTR-255 in addition to CD19-directed CAR T-cell therapy demonstrated a complete response rate of 73 percent at six months, compared to just 50 percent in the placebo group. Notably, two patients in the NKTR-255 group who had stable disease or partial responses at the beginning of the trial were able to convert to complete response by six months.

In addition to improving response rates, NKTR-255 was also shown to enhance CAR T-cell kinetics, with the re-expansion of CAR-T cells observed in the central nervous system (CNS) following treatment. This finding is particularly important, as it demonstrates that NKTR-255 can help CAR-T cells maintain their activity in tissues where tumour cells may be more difficult to target. The study also suggested that NKTR-255 influenced the trafficking of lymphocytes to disease tissues, preferentially where clonal cells or blasts were located.

Expanding the scope: immunotherapy combinations

The impact of NKTR-255 extends beyond its use with CAR-T therapies. In addition to enhancing CAR T-cell responses, NKTR-255 has shown promise in combination with other forms of immunotherapy, including checkpoint inhibitors. For example, at the Society for Immunotherapy of Cancer (SITC) conference, Nektar presented data from a Phase II study evaluating NKTR-255 in combination with durvalumab, a checkpoint inhibitor, in patients with locally advanced non-small cell lung cancer (NSCLC).

Radiation-induced lymphopenia, a condition where radiation therapy reduces lymphocyte levels in the blood, is a common problem in cancer treatment. It has been linked to worse overall survival outcomes, particularly in patients with NSCLC. Dr Steven Lin, a researcher involved in the study, presented data showing that NKTR-255 was able to restore lymphocyte counts in patients after chemoradiation. The combination of NKTR-255 and durvalumab resulted in a statistically significant improvement in lymphocyte recovery, which could enhance the overall effectiveness of the checkpoint inhibitor.

“These advancements underscore the broad applicability of NKTR-255 across both liquid and solid tumours. By enhancing immune cell dynamics and recovery, it opens new doors for combination therapies that improve patient outcomes. As we look to the future, therapies like NKTR-255 could serve as vital components in a new generation of oncology treatments, transforming not only how we address complex cancers but also how we design drug development strategies in immuno-oncology,” says Zalevsky.

The advantages of targeting the IL-15 pathway

The key advantage of NKTR-255 lies in its ability to harness the IL-15 pathway, which plays a crucial role in the development, function and survival of immune cells critical for tumour surveillance. Unlike IL-2, another cytokine with similar effects, IL-15 does not activate regulatory T cells (Tregs), which can dampen the immune response. Instead, IL-15 selectively supports effector cells like CD8+ T cells and NK cells, which are more directly involved in the anti-tumour immune response. This makes NKTR-255 a highly promising therapeutic agent, not only in the context of cancer treatment but also in other immune-related conditions.

Future developments

The next steps for NKTR-255 involve further clinical trials to assess its potential in other cancers. Nektar is continuing its Phase I trial with AbelZeta to evaluate NKTR-255 in combination with tumour-infiltrating lymphocytes (TILs) for patients with advanced NSCLC. The company is also collaborating with Merck KGaA to investigate the molecule in combination with Bavencio for bladder cancer, with results expected shortly.

Zalevsky remains optimistic about the potential of NKTR-255: “All in all, the growing body of evidence highlights the broad applicability of our IL-15. As new data emerge, we continue to explore partnering options to continue the NKTR-255 development program.”

In conclusion, NKTR-255 represents a promising new approach to enhancing the effectiveness of CAR T-cell therapy and other immunotherapies. By targeting the IL-15 pathway and improving CAR T-cell persistence, NKTR-255 has the potential to address one of the most pressing challenges in cancer treatment and usher in a new era of more durable and effective immuno-oncology therapies.