Letter to the editor: clinical translation of senolytic immunotherapy: critical considerations for SenoVax™ and beyond

Dear Editor,

We read with interest the work by Ichim et al. showing that “DC vaccination against senescent fibroblasts (SenoVax™) can induce CD8 + T cell regression in several solid tumor models” [1], published in Journal of Translational Medicine. This work bridges cell senescence and cancer immunotherapy and provides promising preclinical proofs-of-concept for novel senolytic immunotherapy. Synergy with immune checkpoint inhibitors further highlights its potential clinical relevance.

We would like to thank the authors for their thorough mechanistic work. However, we caution that as we strive to translate this promising approach into clinical applications, there are several key considerations that require further exploration in future studies.

First, the source of the antigen. The study used fibroblasts senescent in vitro by doxorubicin. It is practical, however, that tumor-associated senescent cells in vivo are a heterogeneous population: senescent cancer cells, endothelial cells, immune cells with potentially different antigens [2]. Will immunity against drug-induced fibroblast senescence antigens be effective against the spectrum of senescence phenotypes in human tumors induced by chemotherapy or radiotherapy? Future studies of lysates from different stimuli and cell types would be helpful.

Second, the production and scaling of this autologous DC vaccine pose a major clinical challenge. The patient-specific senescence cells, lysates and pulsed DCs need to be generated, expensive and time-consuming process [3]. Off-the-shelf platforms such as allogeneic senescent cells lysates and standard antigen-presenting cells or immunodominant shared senescence antigens for peptide/nucleic acid vaccine development may be of interest.

Third, the long term safety profile needs to be carefully evaluated. The authors report no acute autoimmunity, but senescence is a physiological process involved in wound healing and development [4]. The immune damage of physiological sites (e.g. sites of tissue repair) was not investigated. Chronic toxicity studies and tracking specific organ function would support this safety argument.

Finally, translation needs clarification: SenoVax is intended to be standalone therapy or perhaps combination therapy, like current treatments? Its synergies with checkpoint inhibitors are promising. Combining conventional treatments (chemotherapy, radiotherapy) that induce tumor cell senescence (each creating more targets for the vaccine) could define a niche.

In conclusion, Ichim et al. opened a new direction in cancer immunotherapy. Discussions on antigen size, manufacturing, safety and optimal integration will be needed to translate this exciting senolytic approach from murine data into real human therapies.

Sincerely.

Abbreviations

DC

Dendritic Cell

SenoVax™

Senolytic Dendritic Cell Vaccine

LLC

Lewis Lung Carcinoma

SASP

Senescence–Associated Secretory Phenotype

GM

CSF–Granocyte–Macrophage Colony–Stimulating Factor

IL

4–Interleukin–4

IL

6–Interleukin–6

IFN

γ–Interferon–gamma

PD

L1–Programmed Death–Ligand 1

CTLA

4–Cytotoxic T–Lymphocyte–Associated Protein 4

CAR

T–Chimeric Antigen Receptor T–cell

Author contributions

J.X. and Z.W. drafted the manuscript. L.W. and M.C. critically revised the manuscript and approved the final version. All authors contributed equally to the work and have read and approved the published version of the manuscript.

Funding

Not applicable.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

All authors declare to have no conflicts of interest relevant to this study.