NK cell immunotherapy and bispecific antibodies: new frontiers in cancer treatment

Immunotherapy has transformed cancer treatment in the last decade, especially thanks to immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1 or anti-CTLA-4. However, not all patients respond, and many develop acquired resistance or suffer immune-mediated side effects.

In the face of these limits, a new generation of immunological therapies is emerging, with strategies that go beyond conventional T-cell therapy. These include natural killer (NK cell immunotherapy) cell therapies and biospecific antibodies, approaches that offer greater specificity, lower toxicity and new ways to overcome resistant tumours.

NK cells: innate killers with therapeutic potential

NK cells are part of the innate immune system and have the ability to kill tumour or infected cells without the need for classical antigenic recognition, which makes them especially interesting for tumours with low MHC-I expression or that escape the adaptive system.

Why are NK cells relevant in immunotherapy?

• They do not require prior activation by specific antigens.
• They are less likely to cause autoimmune adverse effects.
• They have a favourable safety profile in clinical models.
• They can be genetically engineered, as in NK-CARs.

Current applications in development

1. Universal donor-derived NK cells or cell lines: allowing «off-the-shelf» therapies, unlike autologous CAR-Ts.
2. NK-CAR therapies: combining natural NK cytotoxicity with chimeric receptor-targeted specificity.
3. Itokine- or antibody-boosted NK: to enhance their persistence and activation in vivo.

Biospecific antibodies: a bridge between immune cells and tumours

Biospecific antibodies are designed to simultaneously bind to two different targets. In immunotherapy, their main function is to bring effector cells of the immune system closer to the tumour, facilitating localised and specific immune activation.

Typical mechanism of action

One arm of the antibody binds to a tumour marker (such as CD19, BCMA or HER2) and the other to an effector cell, most commonly the CD3 T-cell receptor. This generates an artificial immune synapse and triggers the destruction of the tumour cell, without the need for classical antigenic recognition.

Complement, not replace: the future of combination immunotherapies

Although these emerging therapies are promising, they are unlikely to completely replace checkpoint inhibitors or CAR-T. Rather, their greatest value lies in the strategic combination: Checkpoint inhibitors + NK-CARs: improve persistence and reduce tumour immunosuppression. Rather, their greatest value lies in the strategic combination:

• Checkpoint inhibitors + NK-CARs: improving persistence and reducing tumour immunosuppression.
• Biospecific antibodies + cytokines: to enhance effector cell activation.
• Sequential therapies: use biospecific antibodies to ‘clear’ the tumour before administering CAR-T or NK therapies.

Conclusion: New weapons in the immunological arsenal

NK cell therapies and biospecific antibodies represent a critical evolution in cancer immunotherapy, especially for patients who do not respond to current approaches. Far from being replacements, these strategies expand the therapeutic range, offering more personalised, safer and more effective treatments.

In the immediate future, we will see a more complex therapeutic ecosystem, where the key will not be to choose a single strategy, but to design rational combinations based on each patient’s tumour biology and immune system. Because cancer is not a single disease. And neither should our immune response be.