Intralesionals for melanoma - some new reports

I was a fan of intralesional therapies for melanoma long before they were used with any frequency in real live melanoma peeps! I first posted about Rose Bengal (the name I much prefer to the current PV-10) in 2012!!  Rose Bengal sustains high response rate in Melanoma patients!!!  These days the medications used intralesionally for melanoma patients has grown.  Even this list isn't comprehensive:

CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 and IL-12 (tavo) -  are also being used

This link, including an update from June of this year, will give you - A zillion more posts on all things intralesional  Now, there are these ~

False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).  Mulder, Stahlie, Verver, et al.  J Surg Oncol.  Jul 2021.

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy and has been approved for the local treatment of unresectable (stage IIIB/C and IVM1a) cutaneous melanoma. During T-VEC treatment, tumor response is often evaluated using [18F]2-fluoro-2-deoxy- d-glucose(FDG) positron emission tomography/computed tomography (PET/CT). In a Dutch cohort (n = 173), almost one-third of patients developed new-onset FDG uptake in uninjected locoregional lymph nodes during T-VEC. In 36 out of 53 (68%) patients with new nodal FDG uptake, nuclear medicine physicians classified this FDG uptake as "suspected metastases" without clinical or pathological confirmation in the majority of patients. These false positive results indicate that new-onset FDG uptake in locoregional lymph nodes during T-VEC treatment does not necessarily reflect progressive disease, but may be associated with immune infiltration. In current clinical practice, physicians should be aware of the high false positive rate of FDG uptake during treatment with T-VEC in patients with melanoma. Therefore, pathological examination of lymph node lesions with new FDG uptake is recommended to differentiate between progressive disease and immune infiltration after treatment with T-VEC.

Given the real (and wonderful) possibility of "by-stander response" - ie the positive response in lesions NOT injected when intralesional therapy is used - why oh why would you assume that uptake visible on scans is progression you silly silly radiology peeps???!!!!  Live and learn people!  Live and learn!

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Jul-Aug 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

Treatment of in-transit melanoma metastases using intralesional PV-10.  Thompson, Saw, Dalton, et al.  Melanoma Res.  June 2021.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.

T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.  Stahlie, Franke, Zuur, et al.  Cancer Immunol Immunother.  August 2021.

Background: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy.

Methods: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time greater than 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR.

Results: A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting greater than 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions.

Conclusions: This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Much like every other treatment in the melanoma arsenal, intralesional therapy (no matter the type you choose) is not a 100% cure nirvana.  Still, to my mind, it is a valuable weapon available to melanoma patients with in-transit lesions and as a supplement to Stage III and IV patients being treated simultaneously with systemic therapy.  As ever, those with the lowest tumor burden do best.  And sadly, nobody does the Even Steven clinical trials I want to see, placing similar patients on the various intralesionals - with and without equivalent systemic therapies - and THEN comparing outcomes!!!!  Why not, oh brilliant researchers?  WHY?????

For what it's worth - c

Intratumoral or Intralesional therapy for melanoma - again. Yep, AGAIN!!! ASCO 2021, here we go!

Intralesional (intratumoral) therapies have come a loooooong way, baby!  I first began reporting on them in 2014.  Here's a link to a zillion articles and posts:  More than you ever wanted to know about intralesional therapy for melanoma! 

As I embark on posting the things I feel are important from ASCO this year, I will add articles I have been collecting on each topic.  We will start here, with all things intralesional ~ 

The following link takes you to a pretty good review of current state of the data regarding intralesional therapy.  PV-10, Toll-like receptor agonists (TLR's), Intratumoral oncolytic viruses - to include:  CAVATAK, Pexastimogene Devacirepvec (Pexa-Vec), HF10, PVS-RIPO, and TVEC are covered.  Lots of interesting charts and trial results/status are covered, including data (when it exists) on combining these therapies with systemic treatments.   

Intratumoral Immunotherapy Update 2019. Hamid, et al. Oncologist March 2020.

And here:

An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions.  Larocca, LeBoeuf, Silk, et al.  Am J Clin Dermatol, 2020 Dec 21.

Talimogene laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (OncovexGM-CSF Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.

There is this:

Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis.  Comito, Leslie, Boos, et al.   J Immunother, 2020 Oct.

Checkpoint inhibitors (CPIs) have demonstrated a heterogenous spectrum of response and disease progression that may not be fully captured by conventional response criteria, such as a limited degree of progression, known as oligoprogression, which could benefit from local treatment. We retrospectively analyzed data from all patients diagnosed with metastatic melanoma, who received CPI between January 2006 and March 2018 at Royal Marsden. We enrolled 36 patients who experienced progression in a maximum of 3 metastatic sites, after achieving disease control from therapy with CPI, and were radically treated with the locoregional approach. We carried out Kaplan-Meier analysis to obtain progression free-survival post-first oligoprogression (PFS-PO1), overall survival (OS) post-first oligoprogression, and OS estimates. The median time to oligoprogression from the start of CPI was 12 months. At a median follow-up of 34 months, the median PFS-PO1 was 32 months, with 50% of patients not progressed at the time of the data cutoff. The median OS-post-first oligoprogression was not reached. At a median follow-up of 52 months (from the first cycle of CPI), the median OS was not reached, with 75% of patients alive at the time of analysis. Univariate and multivariate analyses demonstrated that baseline American Joint Committee on Cancer stage IV M1a or M1b is associated with a longer PFS-PO1 compared with stage M1c or M1d. We observed that local therapy for oligoprogression after CPI can result in durable disease control, suggesting that locoregional treatment should be considered in patients being treated with immunotherapy. However, prospective evaluation, perhaps in randomized trials, is needed. 

And this:

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Feb 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

And finally, there is this from ASCO:

Talimogene laherparepvec with systemic immunotherapy in melanoma: A real-world experience.  Behera, Chen, Song, et al.  ASCO 2021.

Background: Talimogene laherparepvec (TVEC) is an FDA approved oncolytic herpes virus for intralesional therapy in unresectable metastatic melanoma. Real world data is sparse regarding the efficacy of TVEC in combination with other systemic therapies used in melanoma. We present outcomes of the largest single institution observational study of the off-label use of TVEC in combination with systemic immunotherapy.

Methods:  Patients with metastatic melanoma receiving TVEC simultaneously with ipilimumab-nivolumab (Ipi/Nivo) or single agent immunotherapy (either nivolumab or pembrolizumab) were evaluated. The demographics, clinicopathological characteristics, responses to injected lesions and remote metastatic lesions were evaluated. Clinical documentation was used to assess improvement in injected lesion size; time points for initial response and best response were identified. Review of imaging by a radiologist was evaluated to assess responses in remote metastatic lesions.

Results:  A total of 67 patients receiving TVEC from 2016 to 2020 were evaluated, of which 50 remained evaluable after excluding Merkel cell carcinoma, patients on clinical trial, TVEC monotherapy or those on BRAF-MEK inhibitors, and patients lost to follow up. In total, 29 received systemic immunotherapy simultaneously with TVEC and had been followed for at least a year, with a median follow-up time of 34 months (range, 12-56). At the time of analysis, 14 of 29 patients were alive. 6 of the 29 patients had received prior lines of therapy. Four patients received Ipi/Nivo, while 25 patients received monotherapy including 9 on nivolumab and 16 on pembrolizumab. The median number of TVEC doses received was 6 (range, 2-55) with median average TVEC dose being 3.47 ml (0.5-4 ml). Median time to initial local response was 6 weeks, whereas time to best local response was 14 weeks. Overall response rate in the injected target lesions was in 19 (66%), with complete local response (CR) in 12 (41%), partial response (PR) in 7 (24%), and progressive disease (PD) in 8 (28%). The response rate in distant non-injected lesions was 4 out of 16 (25%), 2 of which had previously progressed on prior systemic therapy. Stable disease was observed in 8 (50%) patients, and progression of disease in 4 (25%). The 1-year overall survival rate in patients receiving TVEC with systemic monotherapy was 80%. Progression free survival at 1-year in the monotherapy group was 71.6%.

Conclusions:  This is the largest single institution, real world experience to our knowledge, which assesses the efficacy of TVEC in combination with systemic immunotherapy. Our cohort suggests that TVEC is an effective treatment in combination with systemic immunotherapy, with a better overall survival observed with combination TVEC and anti-PD1 than seen with historical data from clinical trials of anti-PD-1 monotherapy.

As this mix of reports suggests, intralesional therapy can be used in several ways - as a treatment for one stubborn or new lesion in a person otherwise responding to their therapy; as an add on to pembro (Keytruda) or nivo (Opdivo) for folks with a relatively low burden of disease; or full bore combined with the ipi/nivo combo for those with more advanced disease.  The response rates are not 100%, but they are something!  And we all know, every bit helps!

Gonna shoot for getting a post up daily til done with ASCO (family, work and general life obligations withstanding)!  My fearless and determined bestie had the tough job of going through ALL the ASCO reports!!  When searching for intel on TWO cancers, that task is NOT for the faint of heart.  I have gone through his collection and broken them down into topics.  The reports will follow the pattern I have used here:  Collected, but unshared articles, followed by the selection from ASCO 2021, with my thoughts in red. 

I hope they will be of some use to a few of you.  Take good care. - c 

CAVATAK - intralesional therapy derived from the coxsackievirus

Many intralesional therapies, medicine that is injected directly into a tumor, have been found to have some success in melanoma.  We have learned that, at times, they can not only kill the tumor into which they are injected, but "by-stander" tumors as well. First tried in 1975 with the BCG vaccine, things as disparate as IL2, Allovectin-7 (a DNA mixture), T-VEC/OncoVEX (derived from the herpes virus), L19, PV-10 (from the dye Rose Bengal), GM-CSF, and CAVATAK (derived from the coxsackievirus) have been used.  Additionally, some of these intralesionals have been tested combined with systemic immunotherapy.  The idea being that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic immunotherapy.

Here's some background on the process:  Intralesional therapy for melanoma
Here is a brief review as well as reports from a study where T-VEC was combined with pembro, another with T-VEC and ipi, ipi given with IL2, as well as a report from the CALM study [don't you love their names????!!!] in which the coxsackievirus (CAVATAK) was administered singly:  From ASCO 2015: intralesional therapy for melanoma
Here's specifics on T-VEC:   Good News - local and systemic response to T-VEC
Here's the low-down on PV-10:  ASCO 2014: Rose Bengal (PV-10) with additional links
T-VEC combined with ipi: Pick your poison: Weber and Agarwala
     "When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone."

Now....in truth....I am putting this together for my dear friend, Josh....so I am going to focus on an option he is looking at....CAVATAK with ipi.

Here is info from the CAVATAK only, CALM trial:

 Final data from CALM: A phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma.  ASCO - J Clin Oncol 33, 2015.  Andtbacka, Curti, Kaufman, Daniels, et al.

"CVA21 is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21.  Intratumal injection initiates preferential tumor cell infection, cell lysis [death] and enhancement of a systemic anti-tumor immune response.  The CALM study looked at 57 patients with treated or untreated, unresectable Stage IIIC-IV melanoma.  Patients were given injections on study days 1, 3, 5, 8, and 22, then every 3 weeks for a further 6 injections.  Patients showing immune-related progression-free survival or better at 6 months were eligible for 9 additional injections.  RESULTS:  21 of 57 (38%) patients displayed progression free survival at 6 months with median PFS of 4.2 months.  Overall response rate was 28% (16 of 57) with a more than 6 month durable response rate of 19% (11 of 57).  Median time to response was 2.8 months, 1 year survival rate was 75% (43 of 57 patients).  At more than 16 months, median duration of response in responders and median overall survival for all patients was not yet reached.  Most common side effects = Grade 1 fatigue, chills, local injection site reaction, and fever.  No grade 3 or 4 reactions.  Further studies with CVA21 in combination with other immunotherapies are in process."

And this link/synopsis of Weber's "What's new in 2016" talk...discusses what's coming and recent in melanoma care as well as CALM results:  Immunology update webinar for melanoma
Within...this blurb is included:  

Intralesional Immunotherapy With Oncolytic Coxsackievirus A21 (CVA21) 
 Final response and safety data of the open-label, multicenter phaseII CALM (CAVATAK in Late-stageMelanoma) study of intratumoral CVA21 in 57 patients with unresectable stage IIIC/IV melanoma.    The study met its primary endpoint.  22 of 57 (38.6%) evaluable patients with PFS at 6 months.    Median PFS of 4.2 mos.   ORR 28.1%; median TTR 2.8 mos.  1-year survival rate 75.4%.  Median OS and median DOR not reached (16.5 mos follow-up).  Most common AEs were grade 1 fatigue, chills, fever, and injection site reactions; no grade 3/4 AEs observed.  Looks like another promising intralesional therapy.  Will soon have phase 3 study.

A link to one other report:   Viralytics reports positive final results from cavatak phase 2 melanoma trial

Here is a link to:  Intratumoral CAVATAK and ipi trial
Apparently folks will get ipi at 3mg/kg 4 times.  You have to have an injectable tumor (per their criteria) and CAVATAK will be injected 4 specific times and then every three weeks for up to one year.  The study is a Phase 1 trial, sponsored by Viralytics and was started in late 2014. You can't have taken ipi for metastatic melanoma, but you can have taken it as an adjuvant as long as you did not experience a grade 3 toxicity.  Trial is recruiting in California, Oregon and Illinois.

CAVATAK is also being studied in bladder cancer and non-small-cell lung cancer.  There is also a study combining CAVATAK with pembro for melanoma.  Here's the link:  Intratumoral cavatak and pembro trial  Here folks will get CAVATAK injections at specific times up to 19 total injections into "at least one cutaneous, subcutaneous tumor or palpable lymph node amenable to intratumoral injection" and pembro infusions every 3 weeks up to 2 years. Exclusions include:  no corticosteriods, ocular or mucosal melanoma.  No prior anti-PD1 or PDL1.  Also sponsored by Viralytics, recruiting in New Jersey.

Guess that's about all I got.  I have always been a fan of intralesional therapy...telling B that if I ever recur...and have to have some sort of surgery...I was going to beg to have Rose Bengal and lord knows what else...just splashed around in there before they sew me up.  Those who know B can imagine the big blue eye roll that comment gets me....but there you go!!!  Love you, Josh!  - c

More Intralesional therapies for melanoma....abstracts from ASCO 2014

Wrote this post up in June, but with so much new info about anti-PD1 EAP's (from Merck and BMS) as well as the EAP for the ipi/nivo combo and all the other melanoma news...this got put on the back burner.  I still love the idea of intralesional therapy for folks with accessible tumors.  I don't think it will ever be a cure-all, but feel it holds real promise especially when combined with more systemic therapies.  This is what Weber and Ribas had to say about one in their chat:

Injectable therapies
Ribas:  ...a randomized trial of an injectable virus called T-VEC compared with granulocyte-macrophage colony stimulating factor (GM-CSF).

Weber:  ...the responses were 16% vs 2%.  Obviously you don't expect any responses with GM-CSF, so 2% would be essentially zero.  A 16% response rate overall in a patient with injectable local-regional disease plus systemic disease is pretty modest....that is close to being able to show that there are benefits to giving this injectable therapy....Injectable therapies are making a comeback.....eons ago we were injecting BCG, interferon, and IL-2 into local-regional melanoma metastasis.....now there are some interesting drugs, and T-VEC is one of them.  I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipi, or a combination of those....that's where I see intralesional therapy going.

2 abstracts:

Tumor response and patient survival after intralesional therapy with low-dose GM-CSF and IL-2 in metastatic and primary cutaneous melanoma:  An exploratory study.
Abstract c20002, Elias and Sharma

Patients with dermal and subdermal mets, no matter the extent of their disease or previous therapy, were given intralesional GM-CSF once a week for 4-6 weeks. If no complete clinical response was noted at the injection sites, they were then given intralesional IL-2 for the same length of time. 
Results:  4 patients with more than 126 small in-transit mets, each lesion measured a few mm to up to 1 cm.  All had a complete response confirmed pathologically 6-8 weeks after cessation of therapy, with disease free survival of 37-54 months.  Another 3 patients with large sclerotic skin lesions failed to respond to either cytokine.  One of 2 patients with distant mets who also had palpable subdermal tumors had complete response of all mets. This patient is alive and disease free for over 48 months.  Conclusion:  [After examination of the tissues resected after treatment...] Intralesional therapy seemed to utilize the tumor site as a source for tumor-specific antigens giving rise to autoimmunization with strong antitumor response...

A phase I study with LTX-315, an immunogenic cell death inducer, in patients with transdermally accessible tumors.
Abstract 3067, Brunsvig, Aamdal, Kolstad, et al (London and Oslo)

LTX-315 is a chemically modified 9-mer peptide...and induces the release of potent danger signals and tumor-associated antigens.  Preclinical animal studies have demonstrated that treatment of a single tumor with LTX-315 generated systemic anti-tumor immune response that eradicated distant lesions and prevented recurrence following tumor rechallenge.  Patients received weekly ultrasound guided injections of LTX-315 into a single tumor for a max of 6 injections (dosage varied).  14 patients with lymphomas, malignant melanomas or breast cancer were enrolled.  Tumor necrosis was seen in 5 patients.  2 patients had a 50% reduction in tumor volume.   A new intratumoral study at 4 European sites is ongoing.  Clinical trial number - NCT01058616.

Don't forget good old Rose Bengal (PV-10) as well.  Sort of wish my buddy, J, could have had at least one of these injected into any residual tumors while surgeons were meddling around in there!!!  What the heck?  That's a thought for a trial!  When a melanoma patient has to undergo surgery....inject one of these bad boys into any accessible tumor that is not removed!  Why not?  Just a thought! - c

Intralesional IL-2 combined with anti-PD-1 for melanoma - and links to additional intel on intralesional/intratumoral therapies

From the moment I started seeing research about them, I've been a big fan of intralesional therapy ~  drugs injected directly into accessible melanoma tumors.  My Primer for Melanoma Treatment  contains a link that covers a great deal of what is known about them.  As I note there,

Intralesional drugs include (but are not limited to):

CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 -  is also being used

From earlier this year:  In-transit melanoma metastases and PV-10 vs isolated limb perfusion, an update...

There was this update in 2018:  Reports on Intralesionals for melanoma - T-VEC, SD-101, and Dendritic cells

Here are two more reports from 2018:  T-VEC in melanoma, after progression on immunotherapy and BRAFi with good results! 3 case reports... and In-transit melanoma. Two "new" treatment options!

And from this summer, there is this:

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.  Rafei-Shamsabadi, Lehr, von Bubnoff, and Meiss.  Cancer Immunol Immunother. 2019 Aug 17.   

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4⁺ and CD8⁺ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

These are drugs I would certainly try, especially in combination with immunotherapy, should I have the need.  For what it's worth. ~ c

Study on Intralesional Rose Bengal out of Moffitt...we know a bit more about HOW it works!!!

In 2013 I wrote this:  "I first wrote about PV-10 (also known as Rose Bengal, a pretty cheap derivative of fluorescein, that has been used for over 80 years to stain necrotic tissue in the cornea when corneal abrasions are suspected and as an IV diagnostic of liver impairment) being used in melanoma patients in October of 2012.  The study I reported on was one in which Stage 3-4 melanoma patients had up to 4 courses of PV-10 injections into up to 20 cutaneous and subcutaneous tumors.  The cool thing was that not only did many of the injected tumors respond and shrivel, but some tumors at distant sites (even in the lungs) that were NOT injected, shriveled as well!!!"

And this in 2014:  "Intralesional melanoma therapy (A procedure in which the "treatment" is directly injected into superficial tumors and in theory, not only does that tumor die, but "by stander" tumors at more distant sites die too!!!) was first recorded back in 1975.  A 75 year old male with 64 melanoma mets just below the skin, as well as junk in his lungs, had 17 superficial lesions injected with Bacille Calmette-Guerin over a period of 8 months. (BCG is a vaccine against some strains of tuberculosis, but does contain a weakened version of the bacteria itself within it.) In the end, all 17 tumors injected resolved and his pulmonary mets diminished by more than 50%!  However, enthusiasm for BCG as a melanoma treatment waned as patients in subsequent trials experienced anaphylactic reactions and death due to disseminated BCG, and randomized trials failed to replicate significant clinical benefit.

Later, intralesional therapy was tried using all sorts of things.  More recently Allovectin-7, OncoVEX, and PV-10 have demonstrated positive results, killing melanoma at the injected site and systemically.  [Now we also have CAVATAK, an intralesional derived from the Coxsackievirus:  CAVATAK: intralesional therapy derived from the Coxsackievirus]

Allovectin-7, is a soup of DNA, that attempts to change the gene make-up of tumor cells. In a study reported in 2012, it provided a 12% overall response rate with no grade 3 or higher toxicities in patients with stage III/IV melanoma with injectable cutaneous lesions.

OncoVEX is a 2nd generation herpes virus embedded with GM-CSF...a substance that causes the body to make more white cells. (GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.) But, in OncoVEX, it is thought to only replicate in the tumor cells.  The white cells produced in the process kill off the tumor cells.  In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response.  92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months.  Responses were found in patients with all stages and systemic tumors were eradicated in some patients.

Rose Bengal was first utilized in the 1800's to dye fabrics and color the feet of Bengali women red for weddings and celebrations. Later it was used as a staining agent to find corneal lesions and then as an IV preparation to check for impaired liver function.  The "Aha!" moment came in the 1980's when Japanese tests of a "food dye" to determine tumor origin, found dose-dependent survival increases. After a few other sundry studies....PV-10 was born.  It is a 10% Rose Bengal solution, with a 30-minute half-life, excreted via bile. PV-10 is excluded from normal cells, but slips through the cell membrane of cancer cells (liver, breast, melanoma, and others) because their cell walls have a higher lipid content. Once inside, PV-10 triggers lysosomal release (the part of the cell that digests waste), killing the cell in 30-60 minutes. Antigenic tumor fragments are believed to produce the 'bystander effect' leading to immediate reduction in tumor burden and concomitant immunologic activation."

Here is a link to the entire report and others I've posted here:  Info from ASCO 2014 on Rose Bengal (PV-10) and links to more reports

And now....researchers have learned a little more about how it actually works....

Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1.  Liu, Innamarato, Kodumudi, Weber, et al.  Oncotarget. 2016 May 9.

"Intralesional (IL) therapy is under investigation to treat dermal and subcutaneous metastatic cancer. Rose Bengal (RB) is a staining agent that was originally used by ophthalmologists and in liver function studies. IL injection of RB has been shown to induce regression of injected and uninjected tumors in murine models and clinical trials. In this study, we have shown a mechanism of tumor-specific immune response induced by IL RB. In melanoma-bearing mice, IL RB induced regression of injected tumor and inhibited the growth of bystander lesions mediated by CD8+ T cells. IL RB resulted in necrosis of tumor cells and the release of High Mobility Group Box 1 (HMGB1), with increased dendritic cell (DC) infiltration into draining lymph nodes and the activation of tumor-specific T cells. Treatment of DC with tumor supernatants increased the ability of DCs to stimulate T cell proliferation, and blockade of HMGB1 in the supernatants suppressed DC activity. Additionally, increased HMGB1 levels were measured in the sera of melanoma patients treated with IL RB. These results support the role of IL RB to activate dendritic cells at the site of tumor necrosis for the induction of a systemic anti-tumor immune response."

Bentie has always believed that dendritic cells are going to hold some important keys to understanding and perhaps treating melanoma!  Way to go ratties (and little melanoma-bearing mice)! - c

ASCO 2016: New studies! Rose Bengal and Pembro for Stage IV y'all!!! Enrolling! For Stage IIIb/c: PV-10 vs T-VEC.

I've been singing about Rose Bengal for some time!  Recently this study showed a bit about how it works...and there are links to previous posts  Now there is this:

Intralesional rose bengal for treatment of melanoma.  ASCO 2016. #9600.  J Clin Oncol 2016.  Agarwala, Andtbacka, Rice, et al.

Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897

Really love that there is a head to head look at PV-10 vs T-VEC.  The fact that they had to throw chemo in there pisses me off...but...  Love the idea of anti-PD1 with intralesionals.  Many researchers have been looking at this as the best way to use intralesional therapy.  

And then there's this:  Rose Bengal and Radiation....Overall response rate of 87%!

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.  ASCO 2016. # e21072.  J Clin Oncol 34, 2016.  Foote, Burmeister, Thomas, et al.  

Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months.  Size of metastases (less than 10mm) predicted potential for lesion complete response. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.

Wow!!! Good luck, ratties! - c