Accelerating progress for brain lymphoma: how can ‘immune-activating’ radiotherapy improve CAR-T outcomes?
Primary supervisor: Claire Roddie, University College London
Secondary supervisor: Erik Sahai, The Francis Crick Institute
Project
Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) confers a dismal prognosis with conventional chemotherapeutics, with an OS of <3-6months for most patients. Whole brain radiotherapy (RT) has a role in r/r CNSL, controlling disease where chemotherapy has failed, but is a palliative intervention with short duration response, and treatment dose RT is commonly complicated by significant neurocognitive toxicity including immobility/dementia.
Whilst intravenous (IV) CD19-directed Chimeric antigen receptor T-cell therapy (CAR-T) is highly effective for systemic B-cell lymphoma, for r/r CNSL we and others have shown high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion1,2.
To date, studying the mechanisms underlying suboptimal clinical trial responses to IV CAR-T in CNSL is challenging due to lack of feasibility/safety/ethics of repeat brain biopsy/sampling at relapse. However, two proposed mechanisms include (1) impaired CAR-T trafficking from the systemic circulation into the CNS, due partly to the physical barrier of the blood brain barrier (BBB), and (2) the inhibitory effect of the immune-privileged CNS (tumour) microenvironment (TME) ‘switching off’ incoming CAR-T cells.
Preclinical data in murine models of cancer suggests that ‘immune-activating’ low-dose RT in combination with CAR-T therapy can improve CAR-T trafficking and anti-tumour activity in the immunosuppressive TME3. To date, whilst this combination has not been tested in CNSL, RT has been shown by other groups to increase the permeability of the BBB in relation to drug delivery4.
Here the student will test whether ‘immune-activating’ low-dose RT can mediate enhanced BBB permeability and CAR-T delivery into the CNS in an immunocompetent CNSL murine model we have developed in our lab. Using state-of-the-art imaging mass cytometry, cyclic fluorescence, and scRNAseq expertise (supervised by Dr Erik Sahai Lab) the student will interrogate RT-exposed vs RT-naïve murine CNSL samples derived from in vivo experiments for immune signatures that are associated with ‘immune-activating’ low-dose RT. Integrated spatial and transcriptomic analysis will be performed, with particular attention paid to the spatial distribution and local neighbourhoods of the CAR-T cells. Proteomics will also be used for additional biological insights to further inform engineering approaches.
Once the analysis is complete, the student will engineer CAR-T constructs with modules designed to exploit/resist immune pathways identified by imaging and transcriptomic analysis post-RT (including checkpoints/ cytokines/ chemokine axes) to enable more effective CAR-T entry into the brain/tumour and better function in the CNS.
The advantage of engineering CAR-T with pro-trafficking and pro-activation modules identified through proteomics is that the potential functional benefits are durable and ongoing rather than time-limited and restricted to the absolute period of RT administration.
Further, engineered CAR-T solutions to impaired CNS trafficking/activation in combination with low-dose RT may prove to be synergistic, amplifying CAR-T infiltration, activity and efficacy in this challenging condition beyond what is possible with RT or engineering solutions alone.
Beyond CNSL, the goal is to take lessons learned here and apply in our other brain tumour models, namely glioblastoma
Candidate background
We are particularly interested in receiving applications from candidates with an interest in cellular immunotherapy, radiation biology, murine modelling and analysis of big data.
Potential Research Placements
- Erik Sahai, The Francis Crick Institute
- Silvia Suriniva, University College London
- Maria Hawkins, University College London
References
- Epperla N, Feng L, Shah NN, Fitzgerald L, Shah H, Stephens DM, et al. Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study. J Hematol Oncol. 2023 Nov 9;16(1):111.
- Inc MG. SAFETY AND EFFICACY FINDINGS OF AUTO1, A FAST-OFF RATE CD19 CAR, IN… by Claire Roddie [Internet]. [cited 2022 Dec 21]. Available from: https://library.ehaweb.org/eha/2022/eha2022-congress/358317/claire.roddie.safety.and.efficacy.findings.of.auto1.a.fast-off.rate.cd19.car.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Droddie
- Quach HT, Skovgard MS, Villena-Vargas J, Bellis RY, Chintala NK, Amador-Molina A, et al. Tumor-Targeted Nonablative Radiation Promotes Solid Tumor CAR T-cell Therapy Efficacy. Cancer Immunol Res. 2023 Oct 4;11(10):1314–31.
- van Vulpen M, Kal HB, Taphoorn MJB, El-Sharouni SY. Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review). Oncol Rep. 2002;9(4):683–8.