Sunday, March 29, 2015

Radiation for melanoma...better when combined with immunotherapy!

More and more clarifying data have researchers convinced that abscopal effects and better patient outcomes when radiation is combined with a variety therapies are very real.  Now they are working to figure out HOW it happens, so that it can happen for more people.  Here's a roundup of some of the latest research:

Here's a link to a post from an article that speaks to the benefit of combining SRS with PD1 blockade:  srs-combined-with-anti-pd1-makes-things-better! (for mice at least)

Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice.  Deng, Liang, Burnette, et al.  The Journal of Clinical Investigation, Feb. 2014. 
High dose...radiation results in direct tumor cell death...augments tumor-specific immunity, which enhances tumor control...locally and distantly.  Unfortunately, local relapses often occur [after radiation] indicating that [radiation] induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator PD-L1 can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors.  [These researchers] demonstrate that PD-L1 was upregulated [around the tumor] after radiation.  Concomitant with tumor regression from radiation, they noted that radiation and anti-PD-L1 worked together to reduce the local accumulation of tumor-inflitrating myeloid-derived suppressor cells (MDSCs)... {Note:  Remember, these are the bad guys that block your T cells.  In my study, the folks with high levels of MDSCs did least well, while those with the lowest levels did better.  That's why, some researchers, like Weber, are talking about depleting these cells in patients FIRST...then administering anti-PD1 or other immunotherapies!!}  So...the data acquired in this study demonstrated evidence of the interaction between radiation and T cells....and a basis for the rational design of combination therapy with immune modulators and radiotherapy.

Radiotherapy and Immunogenic Cell Death.  Golden and Apetoh.  Seminars in Radiation Oncology, Jan 2015.
In their review of radiotherapy induced immunogenic cell death....these peeps noted:  Advances in understanding the mechanisms that underlie the interplay between radiation-invoked immune responses and tumor regression are underway.  ...  The dispersion of radiotherapy-induced immune-stimulating tumor antigens released from dying tumor cells into the surround milieu is one such exploitable process that contributes to the propagation of antitumor immunity.  Downstream components of the immune system may suppress, promote or ambiguously affect antitumoral responses.

Combination of Radiotherapy and Immune Checkpoint Inhibitors.  Pilones, Vanpoiulle-Box, and Demaria.  Seminars in Radiation Oncology.  Jan 2015
...only recently [the ability of radiation to cause cell death and inflammatory reactions] has attracted the attention of immunologists seeking to induce or improve antitumor immunity.  As immune checkpoint inhibitors are becoming mainstream cancer treatments, radiation oncologists have begun to observe unexpected out-of-the-field (abscopal) responses in patients receiving radiation therapy during immunotherapy.  These unexpected responses were predicted by experimental work in preclinical tumor models and have clear biological bases.  ....evidence that radiation induces an immunogenic cell death and promotes recruitment and function of T cells within the tumor microenvironment supports the hypothesis that radiation can convert the tumor into an in situ individualized vaccine.  This property of radiation is key to its synergy with immune checkpoint inhibitors, antibodies targeting inhibitory receptors on T cells such as cytotoxic T lymphocyte antigen-4 and programmed death 1.  By removing obstacles hindering the activation and function of antitumor T cells, these agents benefit patients with pre-existing antitumor immunity but are ineffective in patients lacking these spontaneous responses.  Radiation induces antitumor T cells complementing the activity of immune checkpoint inhibitors.

Stereotactic Radiosurgery for Melanoma Brain Metastasis in Patients Receiving Ipilimumab:  Safety Profile and Efficacy of Combined Treatment.  Kiess, Wolchok, Baker, et al.  Int J Radiat Oncol Biol Phys. 2015 March. 
Ipi is a monoclonoal antibody against cytotoxic T-lymphocyte antigen-4, and has been shown to improve survival in patients with metastatic melanoma.  From 2005 - 2011, 46 patients with melanoma were given ipi and SRS for brain mets.  Radiation was a single dose.  Ipi was given at 3 or 10 mg/kg for 4 doses.  15 patients had SRS during ipi.  19 had SRS before ipi.  12 had SRs after ipi.  Patients treated with SRS during or before ipi had better overall survival and less regional recurrence.  (1 year OS = 65% vs 56% vs 40%.  1 year regional recurrence = 69% vs 64% vs 92%)  On MRI, an increase in BM diameter up to more than 150% was seen in 50% of patients treated during or before ipi, but in only 13% of patients treated after ipi.  Overall, ipi and SRS were well tolerated and concurrent delivery of ipi and SRS is associated with favorable locoregional control and possibly longer survival.  It may also cause a temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.  Victor, Rech, Maity, Rengan, et al.  Nature.  March 2015. 
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies....Here we report major tumor regressions in a subset of patients with metastatic melanoma treated with [ipi] and radiation, and reproduced this effect in mouse models.  Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common....analysis of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion.  ...Ipi (anti-CTLA4) inhibits T reg cells, thereby increasing the CD8 T cell to T reg ration.  Radiation enhances the diversity of the T cell receptor repertoire of intratumoral T cells.  Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages ....T cell expansion.  Like the mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed.  Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4 based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

From mice to ratties and back to mice again. Thanks to both, the mechanism and chain of events stimulated by radiation is becoming clear.  It certainly seems that one should get your radiation BEFORE or DURING ipi (and probably other immunotherapies as well).  While radiation kills some tumor cells directly, perhaps more importantly, it sets off an immune response caused by an influx of tumor cell antigens.  When that response is aided by either anti-PD1, anti-CTLA-4 or both, T reg suppressor cells can be blocked, CD8 fighter T cells are increased, T cell exhaustion can be reversed and the invisible shroud in which melanoma cells like to hide, evaporates.  Despite the incredulity that must be swallowed to acknowledge that a somewhat mystical, minute, but deadly cellular war is being waged within my own sounds good to me!!! - c

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