Dr. Ravi Patel headshot

Ravi Patel, MD, PhD

Bentson Laboratory Research Fellow

Department of Human Oncology

I am a Bentson Radiation Oncology Research Fellow in the Department of Human Oncology. I have an MD and PhD in biomedical engineering from Case Western University. I am pursuing a career as physician-scientist and one day hope to have my own lab. I currently work in the Morris Lab, where I apply my expertise in mathematical modeling, drug delivery and in situ vaccination to a variety of research projects. One project looks at targeting metastatic disease through a combination of killing suppressive immune cells and using systemic immunotherapy agents. An exciting aspect about immunotherapy is that it could potentially work on a variety of cancers. Cancer has the ability to evade the immune system, so if we can figure out how to activate the immune system to recognize someone’s cancer, I think we can use those concepts on a wide variety of tumors.


Resident, University Hospitals of Cleveland, Radiation Oncology (2016)

Intern, Akron General Medical Center, (2013)

MD, Case Western Reserve University, Medicine (2012)

PhD, Case Western Reserve University, Biomedical Engineering (2011)

MS, Case Western Reserve University, Biomedical Engineering (2008)

BSE, Case Western University, Tissue Engineering (2003)

Academic Appointments

Bentson Fellow, Human Oncology (2017)

Selected Honors and Awards

NEOMED Oral Presentation Award (2013)

CTSC Training Grant (2010–2012)

NIH MSTP Training Grant (2004–2010)

IMECE Student Paper Competition Finalist (2004)

Biomedical Engineering Research Award (2003)

REU NSF Fellowship (2002)

CWRU President's Scholarship (1999–2003)

Boards, Advisory Committees and Professional Organizations

ASTRO Corporate Relations Committee (2016–pres.)

American Brachytherapy Society (2015–pres.)

Radiological Society of North America (2012–pres.)

American Society of Radiation Oncology (2012–pres.)

American Association for Cancer Research (2012–pres.)

American College of Radiology (2012–pres.)

Low dose radiation to all sites of disease enhances abscopal responses in immunogically “cold” tumors that don’t normally respond to traditional cancer immunotherapy approaches.

The broad goal of my research focus is to utilize radiation therapy to immunomodulate a tumor microenvironment to enhance the efficacy of immunotherapy treatments in solid tumors. My focus is on translational research first in preclinical models to optimize dosing, timing and efficacy of combination treatments with the goal of translating these findings in the lab to early phase clinical trials in patients. I hope to use data that we gather in the laboratory setting to gain mechanistic insights into how radiation interacts with tumor cells as well as a patient’s immune system. My ultimate goal is to design treatments that will result in improved patient survival and eventual cures in cancer patients with metastatic disease.

Combining Immunotherapy with Molecular Targeted Radionuclide Agents for Therapeutic Benefit

Radiation has been shown to synergize with systemic checkpoint blockade and improve its efficacy in multiple preclinical cancer studies. However, as clinicians when we have tried to translate these results to the clinic to improve outcomes in patients, we have had much more mixed results. There are several explanations for these lackluster results, including increased heterogeneity in spontaneously occurring tumors as well as more difficult to treat bulky and widespread disease in real-life patients compared to small single site disease studied in preclinical models. One strategy to overcome these challenges is to deliver immunomodulatory radiation to all sites of disease in a patient with metastatic cancer. Therefore, we developed a collaborative project with Dr. Jamey Weichert’s laboratory in the Department of Radiology to develop a molecularly targeted radionuclide (MTRT) that can deliver low dose immunomodulatory radiation to all sites of disease in patients with metastatic cancer. This MTRT agent, NM600, can be chelated to several different radionuclides to tailor radiation dose rate and delivery to different types of tumors. Moreover this MTRT agent has selective uptake into almost all tumor types, including more than 70 human and mouse tumors that have been tested. Preclinical work that I have led has shown that 90Y-NM600 MTRT has selective uptake into tumors and can improve the efficacy of immune checkpoint blockade in models that do not normally respond to this therapy. We are looking forward to translating this therapy into the clinic to help improve outcomes in patients.


Identification and Characterization of a Novel Synergistic Interaction Between Radiation and the Immune Response to Immune Stimulatory Nanoparticles in Murine Tumor Models

Combination of radiation and innateimmunity stimulating nanoparticles is an area of significant research interest for in situ vaccination strategies. However, the potential interaction between radiation and the immune response to such nanoparticle therapies has not been thoroughly investigated. I am leading a collaborative project between the Morris Lab and Gong Lab in Biomedical Engineering to investigate a novel smart polymer particle that stimulates the innate immune system. This particle is composed of a bacterial membrane, toll-like receptor 9 agonist, and STING agonist that are combined to enhance uptake of cancer antigens into antigen presenting cells (APCs), activate APCs, and then prime adaptive immunity T-cells to create an anti-tumor effector immune response. Using intratumoral injection ofthese smart nanoparticles following local radiation we demonstrated an in situ tumor vaccination effect capable of augmenting tumor response rates in multiple preclinical tumor models.


  • Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade
  • Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice
  • Combination of radiation therapy, bempegaldesleukin, and checkpoint blockade eradicates advanced solid tumors and metastases in mice
  • Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy
  • Combination of Bempegaldesleukin and Anti-CTLA-4 Prevents Metastatic Dissemination After Primary Resection or Radiotherapy in a Preclinical Model of Non-Small Cell Lung Cancer
  • Depth of tumor implantation affects response to in situ vaccination in a syngeneic murine melanoma model
  • Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model
  • <em>In situ</em> Vaccine Plus Checkpoint Blockade Induces Memory Humoral Response
  • Stereotactic body radiotherapy for benign spinal tumors: Meningiomas, schwannomas, and neurofibromas
  • Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition
  • Stereotactic body radiotherapy for oligometastatic renal cell carcinoma-are we ready to roll?
  • Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial-Membrane-Coated Nanoparticles
  • Preclinical Characterization of <sup>86/90</sup>Y-NM600 in a Variety of Murine and Human Cancer Tumor Models
  • Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities
  • Commentary: Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors
  • Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities
  • Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma
  • Complications from Stereotactic Body Radiotherapy for Lung Cancer
  • Comparison of Ray Tracing and Monte Carlo Calculation Algorithms for Thoracic Spine Lesions Treated With CyberKnife-Based Stereotactic Body Radiation Therapy
  • Noninvasive characterization of the effect of varying PLGA molecular weight blends on in situ forming implant behavior using ultrasound imaging
  • Advances in image-guided intratumoral drug delivery techniques
  • Differentiation of benign periablational enhancement from residual tumor following radio-frequency ablation using contrast-enhanced ultrasonography in a rat subcutaneous colon cancer model
  • Effect of injection site on in situ implant formation and drug release in vivo
  • Characterization of formulation parameters affecting low molecular weight drug release from in situ forming drug delivery systems
  • Noninvasive characterization of in situ forming implants using diagnostic ultrasound
  • Model simulation and experimental validation of intratumoral chemotherapy using multiple polymer implants
  • Modeling doxorubicin transport to improve intratumoral drug delivery to RF ablated tumors
  • Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model. J Immunother Cancer
    Baniel CC, Sumiec EG, Hank JA, Bates AM, Erbe AK, Pieper AA, Hoefges AG, Patel RB, Rakhmilevich AL, Morris ZS, Sondel PM
    2020 Oct; 8 (2):
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      BACKGROUND: Some patients with cancer treated with anticancer monoclonal antibodies (mAbs) develop antidrug antibodies (ADAs) that recognize and bind the therapeutic antibody. This response may neutralize the therapeutic mAb, interfere with mAb effector function or cause toxicities. We investigated the potential influence of ADA to modify the tumor-binding capability of a tumor-reactive 'immunocytokine' (IC), namely, a fusion protein (hu14.18-IL2) consisting of a humanized, tumor-reactive, anti-GD2 mAb genetically linked to interleukin 2. We characterize the role of treatment delivery of IC (intravenous vs intratumoral) on the impact of ADA on therapeutic outcome following IC treatments in an established antimelanoma (MEL) regimen involving radiotherapy (RT) +IC.

      METHODS: C57BL/6 mice were injected with human IgG or the hu14.18-IL2 IC to develop a mouse anti-human antibody (MAHA) response (MAHA+). In vitro assays were performed to assess ADA binding to IC using sera from MAHA+ and MAHA- mice. In vivo experiments assessed the levels of IC bound to tumor in MAHA+ and MAHA- mice, and the influence of IC route of delivery on its ability to bind to B78 (GD2+) MEL tumors.

      RESULTS: MAHA is inducible in C57BL/6 mice. In vitro assays show that MAHA is capable of inhibiting the binding of IC to GD2 antigen on B78 cells, resulting in impaired ADCC mediated by IC. When B78-bearing mice are injected intravenously with IC, less IC binds to B78-MEL tumors in MAHA+ mice than in MAHA- mice. In contrast, when IC is injected intratumorally in tumor-bearing mice, the presence of MAHA does not detectibly impact IC binding to the tumor. Combination therapy with RT+IT-IC showed improved tumor regression compared with RT alone in MAHA+ mice. If given intratumorally, IC could be safely readministered in tumor-bearing MAHA+ mice, while intravenous injections of IC in MAHA+ mice caused severe toxicity. Histamine levels were elevated in MAHA+ mice compared with MAHA- mice after reintroduction of IC.

      CONCLUSIONS: Intratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.

      View details for PubMedID 33115944
  • In situ Vaccine Plus Checkpoint Blockade Induces Memory Humoral Response. Front Immunol
    Baniel CC, Heinze CM, Hoefges A, Sumiec EG, Hank JA, Carlson PM, Jin WJ, Patel RB, Sriramaneni RN, Gillies SD, Erbe AK, Schwarz CN, Pieper AA, Rakhmilevich AL, Sondel PM, Morris ZS
    2020; 11: 1610
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      In a syngeneic murine melanoma (MEL) model, we recently reported an in situ vaccination response to combined radiation (RT) and intra-tumoral (IT) injection of anti-GD2 hu14. 18-IL2 immunocytokine (IC). This combined treatment resulted in 71% complete and durable regression of 5-week tumors, a tumor-specific memory T cell response, and augmented response to systemic anti-CTLA-4 antibody checkpoint blockade. While the ability of radiation to diversify anti-tumor T cell response has been reported, we hypothesize that mice rendered disease-free (DF) by a RT-based ISV might also exhibit a heightened B cell response. C57BL/6 mice were engrafted with 2 × 106 GD2+ B78 MEL and treated at a target tumor size of ~200 mm3 with 12 Gy RT, IT-IC on day (D)6-D10, and anti-CTLA-4 on D3, 6, and 9. Serum was collected via facial vein before tumor injection, before treatment, during treatment, after becoming DF, and following rejection of subcutaneous 2 × 106 B78 MEL re-challenge on D90. Flow cytometry demonstrated the presence of tumor-specific IgG in sera from mice rendered DF and rejecting re-challenge with B78 MEL at D90 after starting treatment. Consistent with an adaptive endogenous anti-tumor humoral memory response, these anti-tumor antibodies bound to B78 cells and parental B16 cells (GD2-), but not to the unrelated syngeneic Panc02 or Panc02 GD2+ cell lines. We evaluated the kinetics of this response and observed that tumor-specific IgG was consistently detected by D22 after initiation of treatment, corresponding to a time of rapid tumor regression. The amount of tumor-specific antibody binding to tumor cells (as measured by flow MFI) did not correlate with host animal prognosis. Incubation of B16 MEL cells in DF serum, vs. naïve serum, prior to IV injection, did not delay engraftment of B16 metastases and showed similar overall survival rates. B cell depletion using anti-CD20 or anti-CD19 and anti-B220 did not impact the efficacy of ISV treatment. Thus, treatment with RT + IC + anti-CTLA-4 results in adaptive anti-tumor humoral memory response. This endogenous tumor-specific antibody response does not appear to have therapeutic efficacy but may serve as a biomarker for an anti-tumor T cell response.

      View details for PubMedID 32849544
  • Stereotactic body radiotherapy for benign spinal tumors: Meningiomas, schwannomas, and neurofibromas. J Radiosurg SBRT
    Hwang L, Okoye CC, Patel RB, Sahgal A, Foote M, Redmond KJ, Hofstetter C, Saigal R, Mossa-Basha M, Yuh W, Mayr NA, Chao ST, Chang EL, Lo SS
    2019; 6 (3): 167-177
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      Stereotactic body radiation therapy (SBRT) is a relatively new technology, and its use among patients with benign spinal tumors has limited prospective data. Similar to intracranial benign tumors treated successfully with SBRT, benign spinal tumors of the same histology can also develop, and SBRT may be an effective treatment alternative in inoperable or recurrent cases. Outcomes in patients with neurofibromatosis type 1, neurofibromatosis type 2, or schwannomatosis treated with SBRT have also been reported. Single institution reports have shown local control rates over 90% and improvement in clinical symptoms. The optimum dose and fractionation to maximize local control and minimize toxicity is unknown, with few incidences of radiation treatment-related toxicities. Given the location and benign nature of these tumors, careful management of dose to critical organs is essential. With continued follow-up, the optimum use of SBRT in patients with benign spinal tumors can be better defined.

      View details for PubMedID 31998537
  • Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. J Immunother Cancer
    Voeller J, Erbe AK, Slowinski J, Rasmussen K, Carlson PM, Hoefges A, VandenHeuvel S, Stuckwisch A, Wang X, Gillies SD, Patel RB, Farrel A, Rokita JL, Maris J, Hank JA, Morris ZS, Rakhmilevich AL, Sondel PM
    2019 12 06; 7 (1): 344
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      BACKGROUND: Unlike some adult cancers, most pediatric cancers are considered immunologically cold and generally less responsive to immunotherapy. While immunotherapy has already been incorporated into standard of care treatment for pediatric patients with high-risk neuroblastoma, overall survival remains poor. In a mouse melanoma model, we found that radiation and tumor-specific immunocytokine generate an in situ vaccination response in syngeneic mice bearing large tumors. Here, we tested whether a novel immunotherapeutic approach utilizing radiation and immunocytokine together with innate immune stimulation could generate a potent antitumor response with immunologic memory against syngeneic murine neuroblastoma.

      METHODS: Mice bearing disialoganglioside (GD2)-expressing neuroblastoma tumors (either NXS2 or 9464D-GD2) were treated with radiation and immunotherapy (including anti-GD2 immunocytokine with or without anti-CTLA-4, CpG and anti-CD40 monoclonal antibody). Tumor growth, animal survival and immune cell infiltrate were analyzed in the tumor microenvironment in response to various treatment regimens.

      RESULTS: NXS2 had a moderate tumor mutation burden (TMB) while N-MYC driven 9464D-GD2 had a low TMB, therefore the latter served as a better model for high-risk neuroblastoma (an immunologically cold tumor). Radiation and immunocytokine induced a potent in situ vaccination response against NXS2 tumors, but not in the 9464D-GD2 tumor model. Addition of checkpoint blockade with anti-CTLA-4 was not effective alone against 9464D-GD2 tumors; inclusion of CpG and anti-CD40 achieved a potent antitumor response with decreased T regulatory cells within the tumors and induction of immunologic memory.

      CONCLUSIONS: These data suggest that a combined innate and adaptive immunotherapeutic approach can be effective against immunologically cold syngeneic murine neuroblastoma. Further testing is needed to determine how these concepts might translate into development of more effective immunotherapeutic approaches for the treatment of clinically high-risk neuroblastoma.

      View details for PubMedID 31810498
  • Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial-Membrane-Coated Nanoparticles. Adv Mater
    Patel RB, Ye M, Carlson PM, Jaquish A, Zangl L, Ma B, Wang Y, Arthur I, Xie R, Brown RJ, Wang X, Sriramaneni R, Kim K, Gong S, Morris ZS
    2019 Sep 16; : e1902626
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      Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically "cold" tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These "cold" tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of "cold" tumors, resulting in a more diversified antitumor T-cell response, yet RT alone rarely results in a systemic antitumor immune response. Therefore, a multifunctional bacterial membrane-coated nanoparticle (BNP) composed of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval is developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an antitumor T-cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor-specific antitumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off-the-shelf therapeutics.

      View details for PubMedID 31523868
  • Preclinical Characterization of 86/90Y-NM600 in a Variety of Murine and Human Cancer Tumor Models. J Nucl Med
    Grudzinski JJ, Hernandez R, Marsh I, Patel RB, Aluicio-Sarduy E, Engle J, Morris Z, Bednarz B, Weichert J
    2019 11; 60 (11): 1622-1628
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      We characterize the in vivo biodistribution and tumor selectivity of 86Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a variety of preclinical cancer models. Methods: Mice bearing flank tumors (representative of lung, pancreatic, prostate, liver, skin, and lymphoid cancers) were injected intravenously with 9.25 MBq of 86Y-NM600 and imaged longitudinally over 4-5 d using small-animal PET/CT. Percentage injected activity per gram (%IA/g) for each volume of interest was measured at each time point for the organs of interest. Mice were euthanized after the final time point, and the tumor and organs of interest were counted with an automatic γ-counter. Absorbed doses delivered by 90Y-NM600 per injected activity (Gy/MBq) were estimated. Mice bearing B78 flank tumors were injected with a prescription of 90Y-NM600 that delivered 2.5 Gy of absorbed tumor dose and was compared with an equivalent absorbed dose delivered via external-beam radiotherapy using tumor volume as a measure of response. Histology and complete blood counts were analyzed in naïve C57BL/6 mice that were injected with 9.25 MBq of 90Y-NM600 at 5, 10, and 28 d after injection. Results: PET imaging showed consistent tumor accumulation and retention across all tumor models investigated, with little off-target retention of NM600 except in the liver, as is characteristic of hepatobiliary metabolism. The tumor uptake was highest in the pancreatic and lymphoid cancer models, reaching peak concentrations of 9.34 ± 2.66 %IA/g (n = 3) and 9.10 ± 0.13 %IA/g (n = 3), respectively, at approximately 40-48 h after injection. These corresponded to tumor dose estimates of 2.72 ± 0.33 Gy/MBq and 2.67 ± 0.32 Gy/MBq, respectively. In the toxicity study, there were no visible signs of acute toxicity by histology, and perturbation of hematologic parameters was transient when observed, returning to pretherapy levels after 28 d. Conclusion: NM600 is a theranostic agent with a unique ability to selectively target a variety of cancer types, presenting a unique opportunity for PET image-guided targeted radionuclide therapy and combination with immunotherapies.

      View details for PubMedID 30954941
  • Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities. Brachytherapy
    Patel RB, Baniel CC, Sriramaneni RN, Bradley K, Markovina S, Morris ZS
    2019 Mar - Apr; 18 (2): 240
  • Commentary: Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors. Neurosurgery
    Okoye CC, Patel RB, Sahgal A, Chang EL, Lo SS
    2019 11 01; 85 (5): E840-E841
  • Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities. Brachytherapy
    Patel RB, Baniel CC, Sriramaneni RN, Bradley K, Markovina S, Morris ZS
    2018 Nov - Dec; 17 (6): 995-1003
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      As immunotherapies continue to emerge as a standard component of treatment for a variety of cancers, the imperative for testing these in combination with other standard cancer therapies grows. Radiation therapy may be a particularly well-suited partner for many immunotherapies. By modulating immune tolerance and functional immunogenicity at a targeted tumor site, radiation therapy may serve as a method of in situ tumor vaccination. In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify an antitumor T cell response. The mechanisms whereby radiation may impact immunotherapy are diverse and include its capacity to simultaneously elicit local inflammation, temporary local depletion of suppressive lymphocyte lineages, enhanced tumor cell susceptibility to immune response, and immunogenic tumor cell death. Emerging data suggest that each of these mechanisms may display a distinct dose-response profile, making it challenging to maximize each of these effects using external beam radiation. Conversely, the highly heterogenous and conformal dose distribution achieved with brachytherapy may be optimal for enhancing the immunogenic capacity of radiation at a tumor site while minimizing off-target antagonistic effects on peripheral immune cells. Here, we review the immunogenic effects of radiation, summarize the clinical rationale and data supporting the use of radiation together with immunotherapies, and discuss the rationale and urgent need for further preclinical and clinical investigation specifically of brachytherapy in combination with immunotherapies. Harnessing these immunomodulatory effects of brachytherapy may offer solutions to overcome obstacles to the efficacy of immunotherapies in immunologically "cold" tumors while potentiating greater response in the context of immunologically "hot" tumors.

      View details for PubMedID 30078541
  • Tobacco Mosaic Virus-Delivered Cisplatin Restores Efficacy in Platinum-Resistant Ovarian Cancer Cells. Mol Pharm
    Franke CE, Czapar AE, Patel RB, Steinmetz NF
    2017 Sep 19; :
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      Platinum resistance in ovarian cancer is the major determinant of disease prognosis. Resistance can first appear at the onset of disease or develop in response to platinum-based chemotherapy. Due to poor response to alternate chemotherapies and lack of targeted therapies, there is an urgent clinical need for a new avenue toward treatment of platinum-resistant (PR) ovarian cancer. Nanoscale delivery systems hold potential to overcome resistance mechanisms. In this work, we present tobacco mosaic virus (TMV) as a nanocarrier for cisplatin for treatment of PR ovarian cancer cells. The TMV-cisplatin conjugate (TMV-cisPt) was synthesized using a charge-driven reaction that, like a classic click reaction, is simple and reliable for large-scale production. Up to ∼1900 cisPt were loaded per TMV-cisPt with biphasic release profiles characterized by a fast half-life (t1) of ∼1 h and slow half-life (t2) of ∼12 h independent of pH. Efficient cell uptake of TMV was observed when incubated with ovarian cancer cells, and TMV-cisPt demonstrated superior cytotoxicity and DNA double strand breakage (DSB) in platinum-sensitive (PS) and PR cancer cells when compared to free cisplatin. The cytotoxicity in PR ovarian cancer cells and overall lower effective dosage requirement makes TMV-cisPt a powerful candidate for improved ovarian cancer treatment strategies.

      View details for PubMedID 28926265
  • Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma. Radiother Oncol
    Werner LR, Kler JS, Gressett MM, Riegert M, Werner LK, Heinze CM, Kern JG, Abbariki M, Erbe AK, Patel RB, Sriramaneni RN, Harari PM, Morris ZS
    2017 09; 124 (3): 418-426
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      BACKGROUND AND PURPOSE: We recently reported a time-sensitive, cooperative, anti-tumor effect elicited by radiation (RT) and intra-tumoral-immunocytokine injection in vivo. We hypothesized that RT triggers transcriptional-mediated changes in tumor expression of immune susceptibility markers at delayed time points, which may explain these previously observed time-dependent effects.

      MATERIALS AND METHODS: We examined the time course of changes in expression of immune susceptibility markers following in vitro or in vivo RT in B78 murine melanoma and A375 human melanoma using flow cytometry, immunoblotting, and qPCR.

      RESULTS: Flow cytometry and immunoblot revealed time-dependent increases in expression of death receptors and T cell co-stimulatory/co-inhibitory ligands following RT in murine and human melanoma. Using high-throughput qPCR, we observed comparable time courses of RT-induced transcriptional upregulation for multiple immune susceptibility markers. We confirmed analogous changes in B78 tumors irradiated in vivo. We observed upregulated expression of DNA damage response markers days prior to changes in immune markers, whereas phosphorylation of the STAT1 transcription factor occurred concurrently with changes following RT.

      CONCLUSION: This study highlights time-dependent, transcription-mediated changes in tumor immune susceptibility marker expression following RT. These findings may help in the design of strategies to optimize sequencing of RT and immunotherapy in translational and clinical studies.

      View details for PubMedID 28893414
  • Complications from Stereotactic Body Radiotherapy for Lung Cancer. Cancers (Basel)
    Kang KH, Okoye CC, Patel RB, Siva S, Biswas T, Ellis RJ, Yao M, Machtay M, Lo SS
    2015 Jun 15; 7 (2): 981-1004
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      Stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage, node negative non-small cell lung cancer (NSCLC) in patients who are either medically inoperable or refuse surgical resection. SBRT has high local control rates and a favorable toxicity profile relative to other surgical and non-surgical approaches. Given the excellent tumor control rates and increasing utilization of SBRT, recent efforts have focused on limiting toxicity while expanding treatment to increasingly complex patients. We review toxicities from SBRT for lung cancer, including central airway, esophageal, vascular (e.g., aorta), lung parenchyma (e.g., radiation pneumonitis), and chest wall toxicities, as well as radiation-induced neuropathies (e.g., brachial plexus, vagus nerve and recurrent laryngeal nerve). We summarize patient-related, tumor-related, dosimetric characteristics of these toxicities, review published dose constraints, and propose strategies to reduce such complications.

      View details for PubMedID 26083933
  • Comparison of Ray Tracing and Monte Carlo Calculation Algorithms for Thoracic Spine Lesions Treated With CyberKnife-Based Stereotactic Body Radiation Therapy. Technol Cancer Res Treat
    Okoye CC, Patel RB, Hasan S, Podder T, Khouri A, Fabien J, Zhang Y, Dobbins D, Sohn JW, Yuan J, Yao M, Machtay M, Sloan AE, Miller J, Lo SS
    2016 Feb; 15 (1): 196-202
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      Stereotactic body radiation therapy (SBRT) is an emerging technology for the treatment of spinal metastases, although the dosimetric impact of the calculation method on spinal dose distribution is unknown. This study attempts to determine whether CyberKnife (CK)-based SBRT using a Ray Tracing (RyTc) algorithm is comparable dosimetrically to that of Monte Carlo (MC) for thoracic spinal lesions. Our institutional CK-based SBRT database for thoracic spinal lesions was queried and a cohort was generated. Patients were planned using RyTc and MC algorithms using the same beam angles and monitor units. Dose-volume histograms of the planning target volume (PTV), spinal cord, esophagus, and skin were generated, and dosimetric parameters were compared. There were 37 patients in the cohort. The average percentage volume of PTV covered by the prescribed dose with RyTc and MC algorithms was 91.1% and 80.4%, respectively (P < .001). The difference in average maximum spinal cord dose between RyTc and MC plans was significant (1126 vs 1084 cGy, P = .004), with the MC dose ranging from 18.7% below to 13.8% above the corresponding RyTc dose. A small reduction in maximum skin dose was also noted (P = .017), although no difference was seen in maximum esophageal dose (P = .15). Only PTVs smaller than 27 cm(3) were found to correlate with large (>10%) changes in dose to 90% of the volume (P = .014), while no correlates with the average percentage volume of PTV covered by the prescribed dose were demonstrated. For thoracic spinal CK-based SBRT, RyTc computation may overestimate the MC calculated average percentage volume of PTV covered by the prescribed dose and have unpredictable effects on doses to organs at risk, particularly the spinal cord. In this setting, use of RyTc optimization should be limited and always verified with MC.

      View details for PubMedID 25633137
  • Noninvasive characterization of the effect of varying PLGA molecular weight blends on in situ forming implant behavior using ultrasound imaging. Theranostics
    Solorio L, Olear AM, Hamilton JI, Patel RB, Beiswenger AC, Wallace JE, Zhou H, Exner AA
    2012; 2 (11): 1064-77
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      In situ forming implants (ISFIs) have shown promise in drug delivery applications due to their simple manufacturing and minimally invasive administration. Precise, reproducible control of drug release from ISFIs is essential to their successful clinical application. This study investigated the effect of varying the molar ratio of different molecular weight (Mw) poly(D,L-lactic-co-glycolic acid) (PLGA) polymers within a single implant on the release of a small Mw mock drug (sodium fluorescein) both in vitro and in vivo. Implants were formulated by dissolving three different PLGA Mw (15, 29, and 53 kDa), as well as three 1:1 molar ratio combinations of each PLGA Mw in 1-methyl-2-pyrrolidinone (NMP) with the mock drug fluorescein. Since implant morphology and microstructure during ISFI formation and degradation is a crucial determinant of implant performance, and the rate of phase inversion has been shown to have an effect on the implant microstructure, diagnostic ultrasound was used to noninvasively quantify the extent of phase inversion and swelling behavior in both environments. Implant erosion, degradation, as well as the in vitro and in vivo release profiles were also measured using standard techniques. A non-linear mathematical model was used to correlate the drug release behavior with polymer phase inversion, with all formulations yielding an R(2) value greater than 0.95. Ultrasound was also used to create a 3D image reconstruction of an implant over a 12 day span. In this study, swelling and phase inversion were shown to be inversely related to the polymer Mw with 53 kDa polymer implants increasing at an average rate of 9.4%/day compared with 18.6%/day in the case of the 15 kDa PLGA. Additionally the onset of erosion, complete phase inversion, and degradation facilitated release required 9 d for 53 kDa implants, while these same processes began 3 d after injection into PBS with the 15 kDa implants. It was also observed that PLGA blends generally had intermediate properties when compared to pure polymer formulations. However, release profiles from the blend formulations were governed by a more complex set of processes and were not simply averages of release profiles from the pure polymers preparations. This study demonstrated that implant properties such as phase inversion, swelling and drug release could be tailored to by altering the molar ratio of the polymers used in the depot formulation.

      View details for PubMedID 23227123
  • Advances in image-guided intratumoral drug delivery techniques. Ther Deliv
    Solorio L, Patel RB, Wu H, Krupka T, Exner AA
    2010 Aug; 1 (2): 307-22
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      Image-guided drug delivery provides a means for treating a variety of diseases with minimal systemic involvement while concurrently monitoring treatment efficacy. These therapies are particularly useful to the field of interventional oncology, where elevation of tumor drug levels, reduction of systemic side effects and post-therapy assessment are essential. This review highlights three such image-guided procedures: transarterial chemoembolization, drug-eluting implants and convection-enhanced delivery. Advancements in medical imaging technology have resulted in a growing number of new applications, including image-guided drug delivery. This minimally invasive approach provides a comprehensive answer to many challenges with local drug delivery. Future evolution of imaging devices, image-acquisition techniques and multifunctional delivery agents will lead to a paradigm shift in patient care.

      View details for PubMedID 22816134
  • Differentiation of benign periablational enhancement from residual tumor following radio-frequency ablation using contrast-enhanced ultrasonography in a rat subcutaneous colon cancer model. Ultrasound Med Biol
    Wu H, Patel RB, Zheng Y, Solorio L, Krupka TM, Ziats NP, Haaga JR, Exner AA
    2012 Mar; 38 (3): 443-53
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      Benign periablational enhancement (BPE) response to thermal injury is a barrier to early detection of residual tumor in contrast enhanced imaging after radio-frequency (RF) ablation. The objective of this study was to evaluate the role of quantitative of contrast-enhanced ultrasound (CEUS) in early differentiation of BPE from residual tumor in a BD-IX rat subcutaneous colon cancer model. A phantom study was first performed to test the validity of the perfusion parameters in predicting blood flow of two US contrast imaging modes-contrast harmonic imaging (CHI) and microflow imaging (MFI). To create a simple model of BPE, a peripheral portion of the tumor was ablated along with surrounding normal tissue, leaving part of the tumor untreated. First-pass dynamic enhancement (FPDE) and MFI scans of CEUS were performed before ablation and immediately, 1, 4 and 7 days after ablation. Time-intensity-curves in regions of BPE and residual tumor were fitted to the function y = A(1-exp[-β{t-t0}])+C, in which A, β, t0 and C represent blood volume, flow speed, time to start and baseline intensity, respectively. In the phantom study, positive linear correlations were noted between A, β, Aβ and contrast concentration, speed and flow rate, respectively, in both CHI and MFI. On CEUS images of the in vivo study, the unenhanced ablated zone was surrounded by BPE and irregular peripheral enhancement consistent with residual tumor. On days 0, 4 and 7, blood volume (A) in BPE was significantly higher than that in residual tumor in both FPDE imaging and MFI. Significantly greater blood flow (Aβ) was seen in BPE compared with residual tumor tissue in FPDE on day 7 and in MFI on day 4. The results of this study demonstrate that qualitative CEUS can be potentially used for early detection of viable tumor in post-ablation assessment.

      View details for PubMedID 22266229
  • Effect of injection site on in situ implant formation and drug release in vivo. J Control Release
    Patel RB, Solorio L, Wu H, Krupka T, Exner AA
    2010 Nov 01; 147 (3): 350-8
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      In situ forming drug delivery implants offer an attractive alternative to pre-formed implant devices for local drug delivery due to their ability to deliver fragile drugs, simple manufacturing process, and less invasive placement. However, the clinical translation of these systems has been hampered, in part, by poor correlation between in vitro and in vivo drug release profiles. To better understand this effect, the behavior of poly(D,l-lactide-co-glycolide) (PLGA) in situ forming implants was examined in vitro and in vivo after subcutaneous injection as well as injection into necrotic, non-necrotic, and ablated tumor. Implant formation was quantified noninvasively using an ultrasound imaging technique. Drug release of a model drug agent, fluorescein, was correlated with phase inversion in different environments. Results demonstrated that burst drug release in vivo was greater than in vitro for all implant formulations. Drug release from implants in varying in vivo environments was fastest in ablated tumor followed by implants in non-necrotic tumor, in subcutaneous tissue, and finally in necrotic tumor tissue with 50% of the loading drug mass released in 0.7, 0.9, 9.7, and 12.7h respectively. Implants in stiffer ablated and non-necrotic tumor tissue showed much faster drug release than implants in more compliant subcutaneous and necrotic tumor environments. Finally, implant formation examined using ultrasound confirmed that in vivo the process of precipitation (phase inversion) was directly proportional to drug release. These findings suggest that not only is drug release dependent on implant formation but that external environmental effects, such as tissue mechanical properties, may explain the differences seen between in vivo and in vitro drug release from in situ forming implants.

      View details for PubMedID 20728486
  • Characterization of formulation parameters affecting low molecular weight drug release from in situ forming drug delivery systems. J Biomed Mater Res A
    Patel RB, Carlson AN, Solorio L, Exner AA
    2010 Aug; 94 (2): 476-84
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      In situ forming implants (ISFI) have shown promise in delivering adjuvant chemotherapy following minimally invasive cancer therapies such as thermal ablation of tumors. Although ISFI systems have been thoroughly investigated for delivery of high molecular weight (Mw) therapeutics, little research has been conducted to optimize their design for delivery of low Mw drugs. This study examined the effect of varying the formulation components on the low Mw drug release profile from a ISFI consisting of poly(D,L-lactide-co-glycolide) (PLGA), fluorescein (model drug), and excipient dissolved in 1-methyl-2-pyrrolidinone (NMP). Effects of varying PLGA Mw, excipient concentration, and drug loading were studied. Additionally, solubility studies were conducted to determine the critical water concentration required for phase inversion. Results demonstrated that PLGA Mw was the most significant factor in modulating low Mw drug release from the ISFI systems. ISFI formulations comprised of a low Mw (16 kDa) PLGA showed a significantly (p < 0.05) lower burst release (after 24 h), 28.2 +/- 0.5%, compared with higher Mw PLGA (60 kDa), 55.1 +/- 3.1%. Critical water concentration studies also demonstrated that formulations with lower Mw PLGA had increased solubility in water and may thus require more time to phase invert and release the drug.

      View details for PubMedID 20186771
  • Noninvasive characterization of in situ forming implants using diagnostic ultrasound. J Control Release
    Solorio L, Babin BM, Patel RB, Mach J, Azar N, Exner AA
    2010 Apr 19; 143 (2): 183-90
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      In situ forming drug delivery systems provide a means by which a controlled release depot can be physically inserted into a target site without the use of surgery. The release rate of drugs from these systems is often related to the rate of implant formation. Currently, only a limited number of techniques are available to monitor phase inversion, and none of these methods can be used to visualize the process directly and noninvasively. In this study, diagnostic ultrasound was used to visualize and quantify the process of implant formation in a phase inversion based system both in vitro and in vivo. Concurrently, sodium fluorescein was used as a mock drug to evaluate the drug release profiles and correlate drug release and implant formation processes. Implants comprised of three different molecular weight poly(lactic-co-glycolic acid) (PLGA) polymers dissolved in 1-methyl-2-pyrrolidinone (NMP) were studied in vitro and a 29 kDa PLGA solution was evaluated in vivo. The implants were encapsulated in a 1% agarose tissue phantom for five days, or injected into a rat subcutaneously and evaluated for 48 h. Quantitative measurements of the gray-scale value (corresponding to the rate of implant formation), swelling, and precipitation were evaluated using image analysis techniques, showing that polymer molecular weight has a considerable effect on the swelling and formation of the in situ drug delivery depots. A linear correlation was also seen between the in vivo release and depot formation (R(2)=0.93). This study demonstrates, for the first time, that ultrasound can be used to noninvasively and nondestructively monitor and evaluate the phase inversion process of in situ forming drug delivery implants, and that the formation process can be directly related to the initial phase of drug release dependent on this formation.

      View details for PubMedID 20060859
  • Model simulation and experimental validation of intratumoral chemotherapy using multiple polymer implants. Med Biol Eng Comput
    Weinberg BD, Patel RB, Wu H, Blanco E, Barnett CC, Exner AA, Saidel GM, Gao J
    2008 Oct; 46 (10): 1039-49
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      Radiofrequency ablation has emerged as a minimally invasive option for liver cancer treatment, but local tumor recurrence is common. To eliminate residual tumor cells in the ablated tumor, biodegradable polymer millirods have been designed for local drug (e.g., doxorubicin) delivery. A limitation of this method has been the extent of drug penetration into the tumor (<5 mm), especially in the peripheral tumor rim where thermal ablation is less effective. To provide drug concentration above the therapeutic level as needed throughout a large tumor, implant strategies with multiple millirods were devised using a computational model. This dynamic, 3-D mass balance model of drug distribution in tissue was used to simulate the consequences of various numbers of implants in different locations. Experimental testing of model predictions was performed in a rabbit VX2 carcinoma model. This study demonstrates the value of multiple implants to provide therapeutic drug levels in large ablated tumors.

      View details for PubMedID 18523817
  • Modeling doxorubicin transport to improve intratumoral drug delivery to RF ablated tumors. J Control Release
    Weinberg BD, Patel RB, Exner AA, Saidel GM, Gao J
    2007 Dec 04; 124 (1-2): 11-9
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      A mathematical model of drug transport provides an ideal strategy to optimize intratumoral drug delivery implants to supplement radiofrequency (RF) ablation for tumor treatment. To simulate doxorubicin transport in non-ablated and ablated liver tumors, a one-dimensional, cylindrically symmetric transport model was generated using a finite element method (FEM). Parameters of this model, the diffusion (D) and elimination (gamma) coefficients for doxorubicin, were estimated using drug distributions measured 4 and 8 days after placing biodegradable implants in non-ablated and ablated rabbit VX2 liver carcinomas. In non-ablated tumor, values of diffusion and elimination parameters were 25% and 94% lower than normal liver tissue, respectively. In ablated tumor, diffusion near the ablation center was 75% higher than non-ablated tumor but decreased to the non-ablated tumor value at the ablation periphery. Drug elimination in ablated tumor was zero for the first four days, but by day 8 returned to 98% of the value for non-ablated tumor. Three-dimensional (3-D) simulations of drug delivery from implants with and without RF thermal ablation underscore the benefit of using RF ablation to facilitate local drug distribution. This study demonstrates the use of computational modeling and optimal parameter estimation to predict local drug pharmacokinetics from intratumoral implants after ablation.

      View details for PubMedID 17900740

Contact Information

Ravi Patel, MD, PhD

600 Highland Avenue Madison,
Madison, WI 53792