Intratumoral (intralesional) therapy and a new guy in town: IL-12 Plasmid Transfection (tavo) with pembro

I've been a fan of incorporating intratumoral/intralesional therapy into melanoma care for some time.  Here's proof:  A zillion articles on intralesional therapy

Now this ~

Intratumoral Immunotherapy-Update 2019.  Hamid, Ismail, Puaznov.  Oncologist.  2020 Mar;25.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.  This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

And this ~

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.  Algazi, Twitty, Tsai, et al.  Clin Cancer Res.  2020 May 6.

Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).

Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.

The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.

The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

And finally, this ~

Insights Into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma.  Vidovic and Giacomantonio.  Cancers (Basel) 2020 May 22. 

 The incidence of cutaneous melanoma, a highly malignant skin cancer, is increasing yearly. While surgical removal of the tumor is the mainstay of treatment for patients with locally confined disease, those with metastases face uncertainty when it comes to their treatment. As melanoma is a relatively immunogenic cancer, current guidelines suggest using immunotherapies that can rewire the host immune response to target melanoma tumor cells. Intralesional therapy, where immunomodulatory agents are injected directly into the tumor, are an emerging aspect of treatment for in-transit melanoma because of their ability to mitigate severe off-target immune-related adverse events. However, their immunomodulatory mechanisms are poorly understood. In this review, we will summarize and discuss the different intralesional therapies for metastatic melanoma with respect to their clinical outcomes and immune molecular mechanisms.

For what it's worth.  Hang tough, ratties!!! - c

ISF35 - the viral vector for a CD40 agonist - used as an intratumoral/intralesional melanoma treatment!!!

On the subject of intratumoral treatment of melanoma - drugs that are injected directly into the tumor, as the prior post on IMO-2125, a TLR agonist discussed, along with ALL these other intralesional/intratumoral therapies covered here:  ASCO 2017: All things intralesional/intratumoral
 - we've learned a couple of things:

1.  These drugs can have significant "by-stander" effect.  Meaning - they can kill not only the tumor they are injected it...but others...distant from the site of the injected tumor.

2.  As many melanoma experts said years ago, they will most likely turn out to be most effective when paired with systemic immunotherapy (as most of the research that is on-going is doing currently.

But...there's another one on the horizon.  It's been a long time in coming.  I posted this back in 2014:

CD40 Antibody therapy for melanoma....another way to activate the immune system?

And now, there's this:

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Singh, Vianden, Cantwell, et al. Nat Commun. 2017 Nov 13.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8⁺ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8⁺ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8⁺ T cells, and an increased ratio of intratumoral CD8⁺ T cells to CD4⁺ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.

A triple-decker approach!!!  I like it!!  Now where is the slick MD Anderson poster boards for this one?????

Fingers crossed, ratties!  Fingers crossed. - c

Reports on Intralesionals for melanoma - T-VEC, SD-101, and Dendritic cells

I have a few posts regarding melanoma that got put a bit on the back burner given the chaos that descended upon my world in August.  In the spirit of waste not, want not - thought I'd finish up the year with the last things that looked interesting in melanoma world ~

I still believe that intralesional therapies, especially when combined with a systemic therapy like Opdivo or Keytruda, are going to prove to be of great benefit to many melanoma patients!!!  Here are a zillion links to prior posts:  Intralesional/intratumoral therapy for Melanoma

Here are prior reports on T-VEC:  T-VEC (Talimogene Laherparepvec) for Melanoma  Now, there's this:

Talimogene Laherparepvec (TVEC) for the Treatment of Advanced Melanoma: A Single-Institution Experience.  Perez, Mirua, Naqvi, et al.  Ann Surg Oncol. 2018 Oct 8.   

Talimogene laherparepvec (TVEC) is an oncolytic herpes virus used as intralesional therapy for patients with unresectable stage IIIB through IV melanoma. We reviewed the standard of care treatment of TVEC at a single institution.  All patients treated with TVEC for advanced melanoma were retrospectively evaluated from 2015 to 2018. Patient demographics, clinicopathologic characteristics, treatment response, and toxicity were reviewed.  Twenty-seven patients underwent therapy with TVEC. Median age was 75 years, and 63% of patients were female. Seventeen (63.0%) patients underwent injections on the lower extremity, four (14.8%) on the upper extremity, four (14.8%) on the head and neck, and two (7.4%) on the trunk. Median number of injections was five. Median follow-up was 8.6 months. Of the 27 patients, 23 patients met the criteria for response analysis with at least 8 weeks follow-up. Ten (43.5%) patients experienced a complete response (CR), three (13.1%) experienced a partial response (PR), and five (21.7%) had stable disease (SD) for an overall response rate of 56.5% (CR + PR) and a disease control rate of 78.3% (CR + PR + SD). Adverse events were mostly limited to mild constitutional symptoms within 48 h of injection. Two patients developed cellulitis treated with oral antibiotics, and one patient underwent excision of a lesion for ulceration and bleeding during therapy. TVEC is an effective and well-tolerated intralesional therapy for patients with unresectable stage IIIB through IV melanoma. A CR was achieved in almost half of patients treated. Disease control is seen in the vast majority.  

SD-101 is another intralesional that is proving to have good results.  Here are prior reports:  SD - 101 in melanoma  Now, this summer, there was this:

SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study.  Ribas, Medina, Kummar, et al. Cancer Discov. 2018 Aug 28.

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8⁺ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.

These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone.

Dendritic cells have been examined in many ways in melanoma care:  Dendritic cells in Melanoma  This study looks at them as an intralesional treatment combined with anti-PD-1 and radiation - in MICE:

Administration of dendritic cells and anti-PD-1 antibody converts X-ray irradiated tumors into effective in situ vaccines. Wang, Zenkoh, Gerelchulum, et al. Int J Radiat Oncol Biol Phys. 2018 Nov 17.  
Danger signals and release of tumor-specific antigens after exposure to ionizing radiation can convert an irradiated tumor into an in situ vaccine. However, radiation alone is not sufficient to induce an effective systemic immune response. In this study, we investigated whether a combination of X-ray irradiation with bone marrow-derived dendritic cell (BM-DC) and anti-PD-1 antibody (αPD1-ab) administration can enhance both local tumor control and the systemic abscopal effect in murine subcutaneous tumor models.

B16/BL6 melanoma and Lewis lung carcinoma (LLC) cells were examined of radiosensitivity and expression of H-2kb and PD-L1 before and after irradiation. The tumor cells were implanted subcutaneously in the left thigh of C57BL/6 mice as primary tumors. BM-DCs were induced from mouse bone marrow cells using GM-CSF and IL-4. The primary tumors were treated with 8 Gy of X-ray, followed by simultaneous intratumoral injection of BM-DCs and intraperitoneal injection of αPD1-ab. To examine the abscopal effect, the same tumor cells were also inoculated in the right thighs as metastatic tumors 4 days after the primary tumor inoculation, and only the primary tumors were treated with the same protocols. In vivo analyses of tumor growth and survival rates as well as in vitro analyses of splenic T-cell proliferation and interferon-γ (INF-γ) release were performed.  
The triple combination treatment of X-ray irradiation with BM-DC and αPD1-ab administration inhibited primary tumor growth and significantly extended the survival time in association with significant increase of T-cell proliferation and INF-γ release. In addition, this triple combination treatment significantly inhibited the growth of metastatic tumors.  The results indicated that BM-DC and αPD1-ab administration led to the conversion of irradiated tumors into effective in situ vaccines. This combination therapy can be a promising approach to develop a novel individualized therapy for patients with solid cancers.

Hang tough ratties!!! - 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

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

IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1

So, one of the MRF peeps put up a bit of an ad for this treatment...not entirely sure why, as that is not usually their role.  Perhaps they were just letting folks looking for a treatment option after failing anti-PD-1 know this trial was enrolling.  But, with so little intel out about this study and so many other options available - it piqued my interest.  It was quickly apparent that it is hard to find much info on it other than the super slick "presentations" made by the company who makes it, Idera, and the company who wants you to join their trial, MD Anderson, like these:

A Phase 1/2 trial of intratumoral (i.t.) IMO-2125 (IMO) in combination with checkpoint inhibitors (CPI) in PD-(L)1-refractory melanoma - out of MD Anderson

Idera Press Release for investors

But, when my intrepid medical researcher, partner in crime and all things got on the case, he found this:  Melanoma News Today - report from April 2017

It reads as follows:

Combining IMO-2125 and Yervoy Shows Promise in Certain Metastatic Melanoma Patients   By:  Daniela Semedo, Melanoma News Today, April 2017.

Combining {Idera's] intratumoral IMO-2125 treatment with Yervoy (ipilimumab) may be a promising treatment approach for patients with metastatic melanoma who are refractory to anti-PD-1 therapies, according to preliminary data from a Phase 1/2 clinical trial.

“We are very pleased with the progress to date in the Phase 1 dose escalation trial of IMO-2125 in combination with ipilimumab, and with the outcomes observed,” Joanna Horobin, Idera’s chief medical officer, said in a press release. (Possibly the one I noted above.)

“IMO-2125 in combination with ipilimumab demonstrated preliminary evidence of meaningful clinical activity in this anti-PD-1 refractory metastatic melanoma patient population which represents a high unmet medical need,” she said.

“All dose levels have been well tolerated and did not exacerbate the safety issues commonly observed with ipilimumab,” Horobin said. “Furthermore, data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”

IMO-2125, a toll-like receptor (TLR) agonist, is designed to activate cells from the innate immune system and induce the production of interferon — a potent activator of the immune system. Together, this is thought to lead to the infiltration of tumor-killing T-cells.

Because tumors have developed a method to impair T-cells from recognizing and attacking them, Idera believes that the drug could work in synergy with known and approved immune checkpoint inhibitors.

The open-label Phase 1/2 study (NCT02644967) was designed to assess the safety and preliminary effectiveness of intratumoral IMO-2125 in combination with the CTLA-4 inhibitor Yervoy or the PD-1 inhibitor Keytruda (pembrolizumab) in patients with metastatic melanoma who progressed after receiving anti-PD-1 therapies.  The study was set to be conducted in two parts: a dose-escalation portion (Phase 1) to evaluate safety and tolerability of multiple dose levels, and a Phase 2 expansion portion to assess efficacy.

While the Phase 1 dose escalation of IMO-2125 in combination with Keytruda is ongoing, the company has now announced that the Phase 1 part assessing IMO-2125 plus Yervoy has met the pre-specified futility assessment, meaning that the combination reached the established efficacy cut-off.

The company announced that all dose levels of IMO-2125 were well tolerated, and that the 8 mg dose level was established as the recommended Phase 2 dose.

Nine participants out of an expected 21 have enrolled in the Phase 2 portion of the trial assessing the objective response rate of IMO-2125 in combination with Yervoy. Data will be compared with historical controls treated with Yervoy alone.

Houston’s MD Anderson Cancer Center will continue to lead the study and will be joined by other clinical sites. Idera expects to have overall response rate (ORR) data early next year.

“I am very encouraged by the tremendous progress that has been made to date to advance us to this important stage in IMO-2125’s development cycle,” said Vincent Milano, Idera’s CEO. “There is a very clear unmet medical need for those patients for whom current checkpoint inhibitor therapies are not providing adequate solutions.

“We are incredibly focused on advancing this program as rapidly as possible for these patients, and we are also looking forward to exploring areas outside of melanoma in which intratumoral IMO-2125 may also serve an important role through its unique mechanism of action within the tumor microenvironment,” he said.

Idera also said it has started meeting with regulatory agencies about the best path to follow to register the combined treatment of IMO-2125 and Yervoy in patients with PD-1 refractory metastatic melanoma.

In addition, the company said the Phase 1 clinical trial evaluating the combined treatment of intratumoral IMO-2125 and Keytruda in PD-1 patients with refractory melanoma is enrolling as planned.  Moreover, a Phase 1 clinical trial evaluating intratumoral IMO-2125 alone (NCT03052205) in multiple tumor types should be enrolling the first patient in coming months.

Hmmm.....  Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and it's 40% response rate, leaving them in desperate need of an effective therapy!  It is also true that I encourage and fully support looking at any and all possible treatments to help them.  Yet, I remain a little puzzled here.  This statement sounds strong, but is substantially lacking in, hmmm....what's the word??????  "...data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”  Oh!  I know what it is....DATA!!!!!!!!!!!!!!!  This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!

An interesting aside:  The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function.  The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work.  And the German word for "droll" (i.e. funny) is "toll"!  The more you know....

While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy!  Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:

ASCO 2017: All things intralesional/intratumoral

If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny?????  Hang tough ratties!  The road is long with lots of tolls!  And I mean LOTS!!! - c

Reviews of T-VEC in melanoma patients: alone, with ipi or with pembrolizumab ~

I have been a fan of intraleional (also referred to as intratumoral) treatment - therapies that are injected directly into melanoma lesions - for a long time.  Here are a bazillion reports: Intralesional therapies for melanoma

While T-VEC is currently the only version with FDA approval, here is a list of some of the drugs most often used:
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

Now this -

Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma.  Chesney, Puzanov, Collichio, et al. Br J Cancer. 2019 Jul 29. 

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single greater than/= to 25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7; ipilimumab, n = 1) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.

We already have this report from 2017:  T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...  where it is noted that:  "...quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials."...

Now, this -

Response to the Rechallenge With Talimogene Laherparepvec (T-VEC) After Ipilimumab/Nivolumab Treatment in Patient With Cutaneous Malignant Melanoma Who Initially Had a Progression on T-VEC With Pembrolizumab.  Afzal, Shirai.  J Immunother. 2019 Mar 29.   Talimogene laherparepvec (T-VEC) is approved for unresected stage III-IV malignant melanoma. T-VEC has a direct cytotoxic effect and enhances the antitumor immunity of host cells. Immune checkpoints inhibitors also enhance the immunity of host cells by increasing the recruitment of antigen-presenting cells or activation and restoration of T-cell functions. Both type of therapies can potentiate the effect of the other therapy. We are reporting a case of T-VEC rechallenge who initially progressed on T-VEC with pembrolizumab but then responded to T-VEC rechallenge after intervening ipilimumab/nivolumab. An 83-year-old man developed a subungual lesion of the left thumb and found to have AJCC V. 7 stage IIIb melanoma. Few months later, he developed axillary lymphadenopathy and multiple subcutaneous nodules (AJCC V. 7 stage IIIc). The patient was started on intralesional rose Bengal and pembrolizumab. After 4 cycles of pembrolizumab with rose Bengal, a positron-emission tomography/computerized tomography scan showed the progression of disease. He was started on T-VEC intralesional injections with concurrent pembrolizumab, however, after 3 T-VEC injections and 2 more cycles of pembrolizumab, there was the progression of disease. Subsequently, ipilimumab/nivolumab was started and patient responded partially. Ipilimumab/nivolumab was held due to toxicity. Eight weeks from the last dose of ipilimumab/nivolumab, he experienced locoregional progression and was rechallenged with T-VEC monotherapy. The patient showed a significant response after second T-VEC injection and continued to show response 6 months since rechallenge. After, initial progression on T-VEC with pembrolizumab, intervening immune checkpoints inhibitors may favorably modify the antitumor immunity and potentiate antitumor effect of T-VEC rechallenge.

Cases like this are so difficult to understand - by the patient - poor soul, mostly - but also:  Did the rechallenge with T-VEC really turn the tide?  Or - did all the other therapies - or ONE of the other therapies - finally kick in and just needed more time to work?  We really can't say.  Patients who have experienced multiple therapies and then finally respond, hold the key to many questions.  I'm just not sure we know what exactly they unlock.

Then, this -

Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.  Andtbacka Collichio, Harrington, et al.  J Immunother Cancer. 2019 Jun 6.

Talimogene laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB-IVM1c melanoma.

Patients were randomized 2:1 to receive intratumoral talimogene laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators.

Of 436 patients in the intent-to-treat population, 295 were allocated to talimogene laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (19.5-29.6) and 18.9 months (16.0-23.7) in the talimogene laherparepvec and GM-CSF arms, respectively . DRR was 19.0 and 1.4%; ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the talimogene laherparepvec and GM-CSF arms, respectively, achieved CR. In talimogene laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene laherparepvec efficacy was more pronounced in stage IIIB-IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis.

In this final planned OPTiM analysis, talimogene laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that talimogene laherparepvec was associated with durable CRs that were associated with prolonged survival.

This is one of those studies that gets on my nerve.  We wouldn't have expected GM-CSF to do much better than it did!!!!  But, I guess it shows what T-VEC can do on its own.

And finally, this:

Intratumoral Immunotherapy-Update. Hamid, Ismail, Puzanov.  Oncologist.  2019 Nov 29.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting greater than/= to6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.

IMPLICATIONS FOR PRACTICE: This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

For those interested, here's a direct link to the abstract above:  Intratumoral Immunotherapy-Update 2019.

So - there you have it. NOW!!!  We need direct head-to-head comparisons of some of these other intralesionals (PV-10, CAVATAK, etc.) to T-VEC.  I also think it is clear that generally, intralesional therapy COMBINED with anti-PD-1 is the way to go - whether you are Stage III or IV.   But, that's just me...

Thanks, ratties.  You change the world! - c

Report on intratumoral IL-2 with intratumoral ipi for nonresectable Stage III/IV melanoma

I first reported on this treatment in this link from ASCO 2015:

ASCO 2015: Intralesional therapy for melanoma

Within, among other reports, there is this:

A phase 1 study of intratumoral injection of ipilimumab and interleukin-2 in patients with unresectable stage III-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Bowen, Meek, Williams, Grossman, et al.

Intratumoral IL-2 is highly effective and well tolerated, but does not generate systemic immunity or response in untreated lesions.  IV ipi lowers the threshold for T cell activation leading to a durable clinical response in a minority of melanoma patients, but is associated with potentially severe toxicities.  Since IV ipi doesn't have tissue distribution, circulating anti-tumor T cells activated by the drug may differ greatly from tumor infiltrating lymphocytes activated by INTRATUMORAL ipi in terms of quantity and quality.  Therefore, we hypothesized that a combination of IT IL-2 and IT ipi would effectively hyperactivate and expand TILs to engender systemic immunity with minimal toxicity.   This phase 1 dose escalation trial for ipi and fixed dose IL-2 involved patients with unresectable stage III/IV melanoma and at least one injectable lesions.  A single lesion in each patient was treated with IL-2 IT TIW for 2 wks, then BIW for 6 wks, with escalating doses of ipi IT weekly for 8 weeks.  RESULTS:  12 patients were treated with 3 ipi dose levels.  Treatments were well tolerated.  The only grade 3 toxicity was injection site/tumor necrosis, not dose limiting.  Other toxicities were grade 1.  An abscopal effect (response in a least 1 NON-injected lesion) was seen in 9/12 patients (75%).  10 patients were evaluable for immune response:  4 with partial regression (40%) and 6 had progressive disease, though later one PD was later found to be a complete response by resection.  The 2 nonevaluable patients had regression of multiple skin lesions.  An increase in the frequency of IFN producing CD8+ T cell was detected in 6/8 abscopal responders.  Tbet+ and granzyme B+ CD8+ T cells were observed in 4/5 and 3/5 responders tested, respectively.  Researchers plan to conduct a phase II trial using IT Ipi/IL-2 in conjunction with systemic immunotherapy.

Above, these researchers state that they are planning to conduct a phase II trial with this treatment process, possibly combined with systemic therapy...but this (below) was recently published:  (I left all author names so you can note the researchers.)

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.  Ray, Williams, Meek, Bowen, Grossmann, Andtbacka, Bowles, Hyngstrom, Leachman, Grossman, Bowen, Holmen, VanBrocklin, Suneja, Khong.  Oncotarget. 2016 Jul 6.

Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.

There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients, an abscopal response was seen in 89%. The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% and 50%, respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.

Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.

Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

So...this appears to be the same 12 patients originally reported on....perhaps with a bit more information upon follow-up...with the abscopal response rate being reported at 89% vs the 75% noted in the earlier report.  Or maybe they just needed to have one more article published for their advancement in academia?  Who knows?  Still looks promising.  Don't know why they haven't done a phase II study.  Though I did find this....a phase II study conducted in Germany with no results publishes as of July 6:  clinicaltrials.gov - intratumoral ipilimumab and interleukin 2

If I find any more intel, I'll let you know!  For what it's worth. - c