Friday, April 29, 2016 1:05:37 AM
And the section of the article I quoted earlier (and below) actually proves AVII’s point that DCVax-L responders may end up being removed due to false disease progression. The example they use in FIGURE 1 is of DC vaccination (Okada. H, Kalinksi P, Ueda R et al (2011)). This patient, by RANO standards WOULD have either been removed at baseline (new growth) or shortly after enrollment as the patient exhibited early pseudo progression shortly AFTER administration of the vaccine.
Within FIG1. (a) T-1 weighted axial images following gadolinium administration in a patient with glioblastoma demonstrating pseudo progressive changes after vaccination with autologous dendritic cells pulsed with glioma associated antigens and administered with poly-ICLC. A new nodular focus of enhancement in the medial right parietal lobe (white arrowhead) consistent with tumor progression prior to administration of vaccination. Note that the original tumor site which is located in the lateral right parietal lobe demonstrates minimal enhancement. (b) 9 weeks after initiating vaccination the site of tumor progression is improved and the original tumor site is stable (c) 17 weeks after the vaccine initiation, the area of progression demonstrates further improvements but the original site of tumor demonstrates significantly increased enhancement (dashed white arrow). Resection of the enhancing tumor site revealed no evidence of mitotically active tumor but a marked infiltrate of CD68+ macrophages and CD8+ T cells.
Other sections of the article:
Complexity of radiographic worsening following immunotherapy.
Given the recent marked increase in the application of immunotherapies for cancer indications, appreciation of the complexity to accurately access response has grown in parallel. On the one hand, radiographic improvements is felt to provide a straight forth indication of anti-tumor effect because immunotherapies do not decrease tumor vessel permeability leading to pseudo response as been observed following anti-angiogenic agents. On the other hand, worsening radiographic findings following the immunotherapy may be more challenging to interpret. Although MRI worsening may reflect underlying tumor progression, at least a subset of patients, early worsening of imaging findings may be followed by subsequent clinical benefit. For such patients, early discountation of immunotherapy therapy due to worsened imaging findings assumed to be progressive underlying tumor may result in premature termination of potentially active therapeutic option. There are two possible explanation for lack of correlation between progressive imaging findings and ultimately therapeutic benefit. First unlike radiation therapy or chemotherapy, which are expected to exert a direct and rapid cytotoxic effect, immunotherapies may exert an indirect anti-tumor effect via induction of anti-tumor immune cell infiltrate which take time to mobilize. Importantly the kinetics of such anti-tumor immune response vary between different types of immunotherapies. Nonetheless, in the situation, some patients may have bona fide tumor progression early in the course of their therapy prior to responding to an immunotherapy. Second, a subset of patients may have a pseudo progression radiographic findings following administration of an immunotherapeutic agent. Potent anti-tumor immune responses inherently elicit inflammatory changes in the tumor microenvironment, including the masccrospoci as well as infiltrative microscopic tumor regions, which may results in increased tumor vessel permeability leading in turn to increased contrast uptake as well as associated edema. Precedent for pseudoprogression radiographic changes has been established for neuro-oncology based on experience following administration of temozolomide chemoradiotherapy for newly diagnosed patients. In this setting, pseudo progression typically peak within 3 months and occurs in 20 - 30% of patients. Appreciation of temozolomide chemoradiation associated pseudo progression was a key factor underlying the widespread adoption of radiologic assessment in neuro-oncology.
A growing number of clinical trials evaluating a wide array of immunotherapies across a spectrum of cancer indications demonstrate that a subset of patients treated with immunocytokines, cancer vaccines, T cell therapies and immune checkpoint inhibitors will achieve a radiographic response, durable stable disease or enhanced survival despite worsening of early imaging findings.
Immune-related response criteria (irRC)
In recognition of the complexities associated with radiographic response assessment for patients undergoing treatment with immunotherapeutics, the immuno-oncology community recently drafted response assessment guidance referred to as the immune-related response criteria (irRC). In particular with regard to early progressive changes and their potential impact on premature discontinuation of therapy the irRC incorporates the following considerations: (1) a longer duration of time may be required for immunotherpies to exert measurable clinical activity at the tumor site compared to cytotoxic therapies; (2) immunotherapies may elicit radiographic response after conventional progressive disease criteria has been met; (3) confirmation of progressive disease may be appropriate prior to discontinuation of immune therapy in some cases; (4) “clinically insignificant” progressive disease such as the development of small new lesions in the presence of other responsive lesions should be allowed; and, (5) clinical benefit should include durable stable disease. Furthermore, the irRC recommend continuation of immunotherapy pending progression for clinically stable patients unless contraindicated medically.
In order to avoid premature termination of immune based therapies prior to their ability to exert a potential therapeutic benefit, the irRC incorporates the novel concept of confirmation of progressive disease prior to therapy discontinuation for patients who are clinically stable. Of note, such early progressive radiographic changes may include either significant enlargement of existing lesions or the development of new lesions. In either case, irRC recommend that in the medically stable patients, progression only be defined once follow-up with imaging confirms radiographic findings that meet criteria for tumor progression. In such cases where radiographic progression is confirmed on follow-up imaging, the assigned actual date of progression should be back-dated to the date that the initial criteria for radiographic progression were met. Although the converse, confirmation of radiographic response is an accepted standard for most response assessments metrics in order to ensure that the continuation of a given therapeutic is justified, confirmation of radiographic progression represents a novel paradigm shift in oncology. The down side of this approach is that therapy discontinuation and initiation of an alternative intervention will be delayed for those patients with early progressive radiographic changes who will not ultimately benefit from the administration of immunotherapy. Nonetheless, continuation of currently prescribed immunotherapy pending confirmation of progression for clinically stable patients offers the potential advantages of more accurately interpreting possible misleading early imaging changes and appears reasonable based on accumulated data suggesting that ultimate clinical benefit may be achieved at least in a subset of such patients. For much of euro-oncology, including patients with either a brain metastases or glioblastoma, durably effective therapeutic interventions are significantly limited; therefore adopting a paradigm of confirmation of radiographic progression among medically stable patients may be justified as a strategy to decrease the possibility of premature discontinuation of a promising therapeutic intervention.
Immunotherapy responses assessment in neuro-oncology (iRANO) criteria
Although the principals underlying the irRC provide important response assessment guidance for ongoing immunotherapy efforts in general medical oncology, modifications of these criteria appear warranted in order to optimally and safely apply such guidance for neuro-oncology patients. Similarly, although the RANO criteria were drafted to provide more effective assessment of response for neuro-oncology patients undergoing therapy in the modern era, RANO alone may not fully address relevant considerations for neuro-oncology patients undergoing immunotherapy treatments. Thus, a multidisciplinary and multi-national group of neuro-oncology experts is currently drafting guidance for response assessments of neuro-oncology patients undergoing immune-based therapies. The immunotherapy response assessment in neuro-oncology (iRANO) criteria will integrate key components of both irRC and RANO in order to take into account important nuances with neuro-oncology patients. A comparison of RANO, irRC and iRANO is summarized in Fig 2. Like irRC, iRANO criteria will also advocate for confirmation of radiographic progression among medical stable patients. However, careful consideration is being included to specify temporal parameters and degree of allowed changes in order to ensure patients safety given potential risk associated with robust immunotherapy changes within the confines of the intracranial space. In addition, iRANO will include guidance for response assessment among patients with either enhancing or non-enhancing tumors. Furthermore, and again in the context of preserving overall patient safety, iRANO will provide guidance on when to consider interrupting administration of an immunotherapy for patients with early radiographic progressive changes. Additional important considerations regarding corticosteroid dosing, the role of advanced MR and PET imaging techniques, the inclusion of metric of neurologic function and overall quality of life, as well as guidance on immunocorrelative parameters to be prioritized in clinical research, will be addressed in the iRANO manuscript. MRI imaging following immunotherapy for neuro-oncolgoy patients, as well as PET imagingapproaches suggest that theses modalities may be of benefit in distinguishing tumor recurrence from pseduoprogression. Growing literature also supports the role of MR spectroscopy to predict inflammatory changes from true tumor progression. Monitoring serial assessment over time using advanced imaging techniques may also prove to be particularly helpful rather than single time point assessments.
It’s important to acknowledge that forthcoming iRANO criteria are intended as “best clinical management” guidance due to lack of sufficient clinical data and that these criteria are fully intended to be an initial set of recommendations with full expectation that the proposed criteria will be amended in the future to further enhance their utility as more significant experience with different types of immunotherapies is achieved for neuro-oncology patients and data from ongoing clinical trials is assessed
Conclusions:
Immune-based therapies offer great hope for cancer patients based on their ability to treat existing tumors as well as generate tumor-specific memory immune response capable of preventing future recurrence. Nonetheless, interpretation of early progression radiographic findings has proven challenging in that at least a subset of patients ultimately achieves meaningful anti-tumor benefit. The immuno-oncology community has recently drafted recommendations to guide treating clinicians when confronted with early radiographic worsening that includes continuation of immunotherapy pending confirmation of progression for clinically stable patients. The immunotherapy response assessment for neuro-oncology (iRANO) criteria are currently in development and will integrate key recommendations from RANO with those of irRC in order to help optimally evaluate the therapeutic potential of different immunotherapeutic approaches for near-oncology patients.
Net net, iRANO is not being used in this trial. And, patients who are responding to therapy in the main arm enrollment may end up being prematurely recording PFS. That's not great for the primary endpoint, but hopefully the patients will end up being long-tail survivors that statistically prove OS, the secondary endpoint.
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