Recently, combining immunotherapy with ADCs has entered clinical research, with growing evidence that ADCs may increase the efficacy of immunotherapy. Its mechanisms are varied, including inducing immunogenic cell death, dendritic cell maturation, increasing T lymphocyte infiltration, enhancing immune memory, and expressing immunomodulatory proteins like PD-L1 and MHC.
Combination of ADC and ICIs
Various HER2-targeted ADCs, such as T-DM1, trastuzumab deruxtecan, and disitamab vedotin, have been combined with ICIs and have demonstrated synergistic enhancement activity.
The KATE2 study is the only published randomized trial of ADC plus ICI, comparing the effects of T-DM1 plus atezolizumab and T-DM1 plus placebo in patients with HER2+ breast cancer. Although the combination did not significantly improve PFS (8.2 vs 6.2 months), a trend of improving PFS was observed in the subgroup of patients with positive PD-L1 expression (8.5 vs 4.1 months). This indicates that increasing ICI in targeted therapy for HER2+ breast cancer may only be beneficial to PD-L1 positive patients.
AS the efficacy of some cancers has significantly improved, some combination therapies may replace the standard care regimen of cytotoxic therapy, such as enfortomab vedotin (Nectin 4-MMAE) and pembrolizumab, which have been tested as first-line drugs (NCT03288545) for patients with locally advanced or metastatic urothelial cancer. In this population, the combination resulted in 73% of ORR and 12.3 months of PFS, which earned it FDA breakthrough therapy designation.
The combination of PD-1 antibody and ADCs targeting TF, TROP2 and CD30 has also shown excellent efficacy in cervical cancer, triple negative breast cancer, Hodgkin and primary mediastinal large B-cell lymphoma, making them a better treatment option, especially in frail and elderly patients at risk of severe chemotherapy toxicity.
In the preclinical model, the combination of belantamab mafodotin and OX40 agonists also led to a synergistic anti-tumor effect, increasing infiltration and activation of T cells and dendritic cells in the tumor. In the DREAMM-5 study (NCT04126200), the combined regimen of belantamab mafodotin is being actively studied. In this study, in addition to PD-1 antibodies, it is also used in combination with various immunotherapeutic drugs, including anti-ICOS antibodies, OX40 agonists and γ-secretase inhibitors. Preliminary results show that the combination of the drug and anti-ICOS antibody has good activity in patients in many pretreated patients.
Role of ADC in Immune Drug Resistance
Growing preclinical evidence suggests that combination regimens can restore immune sensitivity, but no clinical data supports immunotherapy for drug-resistant patients. The expression of receptor tyrosine kinase AXL is related to the secretion of immunosuppressive cytokines, leading to ICI resistance in many tumor types. Therefore, using anti-AXL drugs may prevent or reverse ICI resistance. In the PDX model of ICI-refractory melanoma and non-small cell lung cancer, AXL-specific ADC enapotamab vedotin, PD-1 antibody, and MART-1-specific T cells were tested. ADC enhanced ICI activity by inducing T cell penetration and enhanced antigen presentation, leading to the pro-inflammatory transformation of the TME.
ADC in Combination with Monoclonal Antibody, BsAb and CAR-T Therapy
Polatuzumab vedotin has been shown to enhance the CD20 expression on tumor cells by increasing AKT and ERK signal transduction, supporting its combination therapy with CD20 antibodies (e.g., rituximab) and CD20xCD3 bispecific antibodies (e.g., mosunetuzumab or glofitamab).
In a retrospective study of 51 patients receiving a polatuzumab-based bridging strategy, 3 patients who progressed after polatuzumab treatment achieved remission after CD19 CAR-T therapy. It is not clear whether this is related only to the use of CAR-T therapy. However, according to the same principle of enhanced AKT and ERK signals described above, polatuzumab may increase the expression of CD19. Additionally, the cleavable linker ADCs may help it penetrate TME, thus improving the efficacy of CAR-T therapy.
Novel Immune Antibody Drug Conjugate
ADCs can target cancer cells and regulate the components of TME, such as immune cells or fibroblasts, thus changing the immunoreactivity. To achieve this desired effect, the payload and antibody parts of ADCs have been modified.
To enhance the immunomodulatory properties of ADCs, immunostimulatory antibody conjugates (ISACs) have been designed. This new type of ADC is prepared by replacing traditional cytotoxic payloads with immunostimulatory molecules such as Toll-like receptor (TLR) 7hamp8 or interferon gene stimulator (STIN) agonists. These agonists have shown antitumor activity alone, but their systemic administration can lead to widespread immune overactivation, limiting their tolerance.
Targeted delivery of ISACs prepared by coupling these agonists to antibodies is a strategy to minimize their toxicity. ISACs with different targets, including CEA, HER2, TAA1 and PD-L1, have been evaluated in vivo and in vitro, and these drugs are entering clinical trials (NCT04278144, NCT03696771 and NCT05070247).
In preclinical studies, ISACs have been shown to promote acquired immunity and activate innate immune responses by inducing T cell penetration, myeloid reprogramming, antibody-dependent phagocytosis and persistent immune memory. When used in combination with anti-PD-1 antibodies, these agonists enhance the anti-tumor activity of the TME by reprogramming ICI macrophages and inducing responses in a model resistant to single-drug anti-PD1 therapy. Since both ICIs and ISACs are specifically designed to improve immunoreactivity against cancer cells, their combination has raised concerns about the risk of severe immune-related adverse events. A clinical trial (NCT04278144, NCT05070247) is under way to evaluate the safety and efficacy of ISACs in combination with ICIs.
ADC can also be designed for specific components of the TME, including T lymphocytes and stromal cells. For example, ADCs targeting CD73 have shown excellent preclinical activity. The use of MMAE-conjugated CD73 antibodies in NSCLC and glioma models can lead to a decrease in myeloid-derived suppressor cells, an increase in proinflammatory tumor infiltrating macrophages and mature dendritic cells, and inhibition of tumor growth.
In addition, in a preclinical model, ADCs combined with pembrolizumab for cancer-associated fibroblasts showed enhanced anti-tumor activity mediated by CD8+T cells.
Currently, ADCs targeting the interleukin-2 receptor alpha subunit (CD25) is also used, which is highly expressed by Treg cells. The ADC could lead to the depletion of Treg cells and the increase of CD8+T cells, and showed synergistic activity in combination with anti-PD-1 antibodies. A clinical trial is under way to test the combination of ADCs and pembrolizumab (NCT03621982).