Combined High-Dose LATTICE Radiation Therapy and Immune Checkpoint Blockade for Advanced Bulky Tumors: The Concept and a Case Report

Abstract

Although the combination of immune checkpoint blockades with high dose of radiation has indicated the potential of co-stimulatory effects, consistent clinical outcome has been yet to be demonstrated. Bulky tumors present challenges for radiation treatment to achieve high rate of tumor control due to large tumor sizes and normal tissue toxicities. As an alternative, spatially fractionated radiotherapy (SFRT) technique has been applied, in the forms of GRID or LATTICE radiation therapy (LRT), to safely treat bulky tumors. When used alone in a single or a few fractions, GRID or LRT can be best classified as palliative or tumor de-bulking treatments. Since only a small fraction of the tumor volume receive high dose in a SFRT treatment, even with the anticipated bystander effects, total tumor eradications are rare. Backed by the evidence of immune activation of high dose radiation, it is logical to postulate that the combination of High-Dose LATTICE radiation therapy (HDLRT) with immune checkpoint blockade would be effective and could subsequently lead to improved local tumor control without added toxicities, through augmenting the effects of radiation in-situ vaccine and T-cell priming. We herein present a case of non-small cell lung cancer (NSCLC) with multiple metastases. The patient received various types of palliative radiation treatments with combined chemotherapies and immunotherapies to multiple lesions. One of the metastatic lesions measuring 63.2 cc was treated with HDLRT combined with anti-PD1 immunotherapy. The metastatic mass regressed 77.84% over one month after the treatment, and had a complete local response (CR) five months after the treatment. No treatment-related side effects were observed during the follow-up exams. None of the other lesions receiving palliative treatments achieved CR. The dramatic differential outcome of this case lends support to the aforementioned postulate and prompts for further systemic clinical studies.

An International Consensus on the Design of Prospective Clinical–Translational Trials in Spatially Fractionated Radiation Therapy

“…The inclusion of well-conducted translational science into clinical trial design is critically important to investigate in clinical patients the preclinically observed biological mechanisms and potential immunological phenomena of SFRT [15][16][17][18][19][20] . To accomplish this, "liquid biopsy" concepts, leveraged through serial blood and urine collections, synchronized prospectively with the treatment course, may advance our understanding of the underpinnings of SFRT response.…”

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

“…Lastly, known that lattice radiotherapy delivery has a potentially immunogenic role, such a technique was promisingly tested in combination with immunotherapy in a case report by Jiang et al; they checked if the addition of pembrolizumab is able to enhance the bystander immunomodulatory effect induced by a single high dose fraction of Lattice radiotherapy in a case of pluri-metastatic NSCLC with a bulky cutaneous metastasis. Indeed, they surprisingly reported a complete local response after combined treatment [25]. All the above-mentioned experiences are summarized in Table 1.…”

Microbeam Radiotherapy—A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma

“…The key feature of SFRT in radiation-induced anti-tumour immunity is the peak-valley dose distribution, where the peaks are the regions of high-dose deposition and the valleys are the regions in between which receive relatively low doses [ 35 , 82 ]. This radiation scheme inherently results in the administration of ablative- and low-dose deposition simultaneously.…”

“…Detailed investigations differentiating the degree of inflammation and immune activation following SFRT vs. conventional methods have yet to be performed. It has been postulated that the high doses delivered in the incident or peak regions increase neo-antigen release which ultimately leads to T cell priming, while the low-dose regions in between, maintain circulation and perfusion to facilitate effector and T cell infiltration [ 82 ].…”